Heteroarylmethyl amides

ABSTRACT

The present invention relates to compounds of the formula 
                         
wherein A 1 , A 2 , A 3  and R 1  to R 8  are defined in the description, and to pharmaceutically acceptable salts thereof, their manufacture, pharmaceutical compositions containing them and their use as medicaments for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents, such as particularly dyslipidemia, atherosclerosis and cardiovascular diseases.

PRIORITY TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.13/226,521, filed Sep. 7, 2011, which, in turn, claims the benefit ofpriority to European Patent Application No. 10175984.3, filed Sep. 9,2010, both of which are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present invention is concerned with heteroarylmethyl amide compoundsas HDL-cholesterol raising agents, their manufacture, pharmaceuticalcompositions containing them and their use as therapeutically activesubstances. The compounds of the present invention can be used in thetherapeutic and/or prophylactic treatment of diseases and disorders suchas dyslipidemia, atherosclerosis and cardiovascular diseases.

BACKGROUND OF THE INVENTION

Atherosclerosis and its associated coronary heart disease are theleading cause of death in the industrialized world. Risk for developmentof coronary heart disease has been shown to be strongly correlated withcertain plasma lipid levels. Lipids are transported in the blood bylipoproteins. The general structure of lipoproteins is a core of neutrallipids (triglyceride and cholesterol ester) and an envelope of polarlipids (phospholipids and non esterified cholesterol). There are 3different classes of plasma lipoproteins with different core lipidcontent: the low density lipoprotein (LDL) which is cholesteryl ester(CE) rich; high density lipoprotein (HDL) which is also cholesterylester (CE) rich; and the very low density lipoprotein (VLDL) which istriglyceride (TG) rich. The different lipoproteins can be separatedbased on their different flotation density or size.

High LDL-cholesterol (LDL-C) and triglyceride levels are positivelycorrelated, while high levels of HDL-cholesterol (HDL-C) are negativelycorrelated with the risk for developing cardiovascular diseases.

No wholly satisfactory HDL-elevating therapies exist. Niacin cansignificantly increase HDL, but has serious toleration issues whichreduce compliance. Fibrates and the HMG CoA reductase inhibitors raiseHDL-cholesterol only modestly (−10-12%). As a result, there is asignificant unmet medical need for a well tolerated agent which cansignificantly elevate plasma HDL levels.

Thus, HDL-cholesterol raising agents can be useful as medicaments forthe treatment and/or prophylaxis of atherosclerosis, peripheral vasculardisease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, and vascularcomplications of diabetes, obesity or endotoxemia.

In addition, HDL-cholesterol raising agents may be used in combinationwith another compound, said compound being an HMG-CoA reductaseinhibitor, an microsomal triglyceride transfer protein (MTP)/ApoBsecretion inhibitor, a PPAR activator, a bile acid reuptake inhibitor, acholesteryl ester transfer protein (CETP) inhibitor, a cholesterolabsorption inhibitor, a cholesterol synthesis inhibitor, a fibrate,niacin, preparations containing niacin or other HM74a agonists, anion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acidsequestrant.

It has been found that the compounds of the present invention are usefulfor the treatment and/or prophylaxis of diseases and disorders which canbe treated with HDL-cholesterol raising agents, i.e. the compounds areespecially useful for the treatment and/or prevention of dyslipidemia,atherosclerosis and cardiovascular diseases.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula I,

whereinA¹, A² and A³ are each selected from N and CH, provided that at leastone of A¹, A² and A³ is N and at least one of A¹, A² and A³ is CH;R¹ is selected from the group consisting of lower alkyl,cycloalkyl,lower cycloalkylalkyl,lower hydroxyalkyl,lower alkoxyalkyl,lower halogenalkyl,lower carbamoylalkyl,lower alkylcarbonylaminoalkyl,lower phenylalkyl,lower heterocyclylalkyl wherein the heterocyclyl group is unsubstitutedor substituted by oxo,lower heteroarylalkyl wherein the heteroaryl group is unsubstituted ormono- or di-substituted by lower alkyl, andphenyl which is unsubstituted or mono- or di-substituted by halogen;R² and R⁶ independently from each other are hydrogen or halogen;R³ and R⁵ independently from each other are selected from the groupconsisting of hydrogen, lower alkyl, lower alkoxy, halogen, lowerhalogenalkyl, lower halogenalkoxy and cyano;R⁴ is selected from the group consisting of hydrogen, lower alkoxy,halogen, lower halogenalkyl, lower halogenalkoxy and cyano;or R⁴ and R⁵ together with the C atoms they are attached to form a five-or six-membered carbocycle or a five- or six-membered heterocyclecontaining one, two or three heteroatoms selected from the groupconsisting of N, O and S, said carbocycle or heterocycle beingunsubstituted or substituted by one or two substituents independentlyselected from the group consisting of lower alkyl, lower alkoxy,halogen, lower halogenalkyl, lower halogenalkoxy and cyano;R⁷ and R^(7′) independently from each other are hydrogen or lower alkyl;andR⁸ is a five- or six-membered heteroaryl group containing one, two orthree heteroatoms selected from the group consisting of N, O and S, saidheteroaryl group being unsubstituted or substituted by one or twosubstituents independently selected from the group consisting of loweralkyl, lower alkoxy, halogen, lower halogenalkyl and cycloalkyl;or a pharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical compositioncomprising a compound as described above and a pharmaceuticallyacceptable carrier and/or adjuvant.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein.

In this specification the term “lower” is used to mean a groupconsisting of one to seven, preferably of one to four carbon atom(s).

The term “alkyl”, alone or in combination with other groups, refers to abranched or straight-chain monovalent saturated aliphatic hydrocarbonradical of one to twenty carbon atoms, preferably one to sixteen carbonatoms, in particular one to ten carbon atoms.

The term “lower alkyl” or “C₁₋₇-alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 7carbon atoms, in particular a straight or branched-chain alkyl groupwith 1 to 6 carbon atoms and more particularly a straight orbranched-chain alkyl group with 1 to 4 carbon atoms. Examples ofstraight-chain and branched C₁₋₇ alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls, theisomeric hexyls and the isomeric heptyls, in particular ethyl, propyl,isopropyl and tert-butyl.

The term “lower alkoxy” or “C₁₋₇-alkoxy” refers to the group R′—O—,wherein R′ is lower alkyl and the term “lower alkyl” has the previouslygiven significance. Examples of lower alkoxy groups are methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy andtert.-butoxy, in particular methoxy.

The term “lower alkoxyalkyl” or “C₁₋₇-alkoxy-C₁₋₇-alkyl” refers to alower alkyl group as defined above which is mono- or multiplysubstituted with a lower alkoxy group as defined above. Examples oflower alkoxyalkyl groups are e.g. —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃,—CH₂—O—CH₂—CH₃ and the groups specifically exemplified herein. Moreparticularly, lower alkoxyalkyl is methoxyethyl.

The term “lower hydroxyalkyl” or “hydroxy-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a hydroxy group. Of particularinterest are C₃₋₇-hydroxyalkyl groups. Examples of lower hydroxyalkylgroups are 2-hydroxybutyl, 3-hydroxy-2,2-dimethylpropyl and the groupsspecifically exemplified therein.

The term “cycloalkyl” or “C₃₋₇-cycloalkyl” denotes a saturatedcarbocyclic group containing from 3 to 7 carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, moreparticularly cyclopropyl.

The term “lower cycloalkylalkyl” or “C₃₋₇-cycloalkyl-C₁₋₇-alkyl” refersto lower alkyl groups as defined above wherein at least one of thehydrogen atoms of the lower alkyl group is replaced by a cycloalkylgroup. Among the lower cycloalkylalkyl groups of particular interestresides cyclopropylmethyl.

The term “halogen” refers to fluoro, chloro, bromo and iodo, withfluoro, chloro and bromo being of particular interest. Moreparticularly, halogen refers to fluoro and chloro.

The term “lower halogenalkyl” or “halogen-C₁₋₇-alkyl” refers to loweralkyl groups which are mono- or multiply substituted with halogen,preferably with fluoro or chloro, most preferably with fluoro. Examplesof lower halogenalkyl groups are e.g. —CF₃, —CHF₂, —CH₂Cl, —CH₂CF₃,—CH(CF₃)₂, —CF₂—CF₃, —CH(CH₃)—CF₃ and the groups specificallyexemplified herein. Of particular interest are the groupstrifluoromethyl (—CF₃), 2,2,2-trifluoroethyl (—CH₂CF₃) and1,1,1-trifluoro-propan-2-yl (—CH(CH₃)—CF₃).

The term “carbamoyl” refers to the group —CO—NH₂.

The term “lower carbamoylalkyl” or “carbamoyl-C₁₋₇-alkyl” refers tolower alkyl groups as defined above wherein one of the hydrogen atoms ofthe lower alkyl group is replaced by a carbamoyl group. Examples oflower carbamoylalkyl groups are 3-carbamoylpropyl, 4-carbamoylbutyl and5-carbamoylpentyl, more particularly 4-carbamoylbutyl.

The term “lower alkylcarbonyl” refers to the group —CO—R″, wherein R″ islower alkyl as defined herein before. “Lower alkylcarbonylamino” refersto the group —NH—CO—R″, wherein R″ is lower alkyl as defined hereinbefore.

The term “lower alkylcarbonylaminoalkyl” or“C₁₋₇-alkylcarbonylamino-C₁₋₇-alkyl” refers to lower alkyl groups asdefined above wherein one of the hydrogen atoms of the lower alkyl groupis replaced by a lower alkylcarbonylamino group. An example for a loweralkylcarbonylaminoalkyl group is ethylcarbonylaminoethyl.

The term “lower phenylalkyl” or “phenyl-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a phenyl group. In particular,lower phenylalkyl means benzyl.

The term “heterocyclyl” refers to a saturated or partly unsaturated 3-,4-, 5-, 6- or 7-membered ring which can comprise one, two or threeheteroatoms selected from N, O and S. Examples of heterocyclyl ringsinclude piperidinyl, piperazinyl, azetidinyl, azepinyl, pyrrolidinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, oxiranyl,thiadiazolylidinyl, oxetanyl, dioxolanyl, dihydrofuryl, tetrahydrofuryl,dihydropyranyl, tetrahydropyranyl, and thiomorpholinyl.

The term “lower heterocyclylalkyl” or “heterocyclyl-C₁₋₇-alkyl” refersto lower alkyl groups as defined above wherein at least one of thehydrogen atoms of the lower alkyl group is replaced by a heterocyclylgroup as defined above.

The term “heteroaryl” refers to an aromatic 5- or 6-membered ring whichcan comprise one, two or three atoms selected from N, O and S. Examplesof heteroaryl groups are e.g. furyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, thienyl, isoxazolyl, thiazolyl, isothiazolyl, oxazolyl,imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, oxatriazolyl, tetrazolyl,pentazolyl, or pyrrolyl. The heteroaryl group can optionally be mono- ordisubstituted by lower alkyl, lower alkoxy, halogen, lower halogenalkylor cycloalkyl. Heteroaryl groups of particular interest are oxazolyl,isoxazolyl, pyrazolyl, thiazolyl and [1,2,4]oxadiazolyl.

The term “lower heteroarylalkyl” or “heteroaryl-C₁₋₇-alkyl” refers tolower alkyl groups as defined above wherein at least one of the hydrogenatoms of the lower alkyl group is replaced by a heteroaryl group asdefined above.

The term “carbocycle” refers to non-aromatic or aromatic ring system inwhich all ring atoms are carbon atoms. Carbocycles are cycloalkylgroups, but also aromatic groups such as phenyl.

The term “heterocycle” refers to heterocyclyl and heteroaryl groups asdefined herein before.

“Isomeric forms” are all forms of a compound characterized by having anidentical molecular formula but that differ in the nature or thesequence of bonding of their atoms or in the arrangement of their atomsin space. Preferably, the isomeric forms differ in the arrangement oftheir atoms in space and can also be termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four non-identical substituents is termed a “chiralcenter”.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, and which do not possess any own properties that areundesirable. The salts are formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, preferably hydrochloric acid, and organicacids such as formic acid, acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.Thus, preferred “pharmaceutically acceptable salts” include the acetate,bromide, chloride, formate, fumarate, maleate, mesylate, nitrate,oxalate, phosphate, sulfate, tartrate and tosylate salt of compounds offormula I. In addition, pharmaceutically acceptable salts may beprepared from addition of an inorganic base or an organic base to thefree acid. Salts derived from an inorganic base include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium, magnesiumsalts and the like. Salts derived from organic bases include, but arenot limited to salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, diethylamine, lysine, arginine, N-ethylpiperidine,piperidine, piperazine and the like. The compound of formula I can alsobe present in the form of zwitterions or in the form of hydrates.Particularly preferred pharmaceutically acceptable salts of compounds offormula I are the hydrochloride salts.

The present invention relates to compounds of formula I,

whereinA¹, A² and A³ are each selected from N and CH, provided that at leastone of A¹, A² and A³ is N and at least one of A¹, A² and A³ is CH;R¹ is selected from the group consisting of lower alkyl,cycloalkyl,lower cycloalkylalkyl,lower hydroxyalkyl,lower alkoxyalkyl,lower halogenalkyl,lower carbamoylalkyl,lower alkylcarbonylaminoalkyl,lower phenylalkyl,lower heterocyclylalkyl wherein the heterocyclyl group is unsubstitutedor substituted by oxo,lower heteroarylalkyl wherein the heteroaryl group is unsubstituted ormono- or di-substituted by lower alkyl, andphenyl which is unsubstituted or mono- or di-substituted by halogen;R² and R⁶ independently from each other are hydrogen or halogen;R³ and R⁵ independently from each other are selected from the groupconsisting of hydrogen, lower alkyl, lower alkoxy, halogen, lowerhalogenalkyl, lower halogenalkoxy and cyano;R⁴ is selected from the group consisting of hydrogen, lower alkoxy,halogen, lower halogenalkyl, lower halogenalkoxy and cyano;or R⁴ and R⁵ together with the C atoms they are attached to form a five-or six-membered carbocycle or a five- or six-membered heterocyclecontaining one, two or three heteroatoms selected from the groupconsisting of N, O and S, said carbocycle or heterocycle beingunsubstituted or substituted by one or two substituents independentlyselected from the group consisting of lower alkyl, lower alkoxy,halogen, lower halogenalkyl, lower halogenalkoxy and cyano;R⁷ and R^(7′) independently from each other are hydrogen or lower alkyl;andR⁸ is a five- or six-membered heteroaryl group containing one, two orthree heteroatoms selected from the group consisting of N, O and S, saidheteroaryl group being unsubstituted or substituted by one or twosubstituents independently selected from the group consisting of loweralkyl, lower alkoxy, halogen, lower halogenalkyl and cycloalkyl;and pharmaceutically acceptable salts thereof.

In particular, compounds of the present invention are those according toformula I, wherein

A¹, A² and A³ are each selected from N and CH, provided that at leastone of A¹, A² or A³ is N and at least one of A¹, A² or A³ is CH;

R¹ is selected from the group consisting of

lower alkyl,

cycloalkyl,

lower cycloalkylalkyl,

lower hydroxyalkyl,

lower alkoxyalkyl,

lower halogenalkyl,

lower carbamoylalkyl,

lower alkylcarbonylaminoalkyl,

lower phenylalkyl,

lower heterocyclylalkyl wherein the heterocyclyl group is unsubstitutedor substituted by oxo,

lower heteroarylalkyl wherein the heteroaryl group is unsubstituted ormono- or di-substituted by lower alkyl, and

phenyl which is unsubstituted or mono- or di-substituted by halogen;

R² and R⁶ independently from each other are hydrogen or halogen;

R³ and R⁵ independently from each other are selected from the groupconsisting of hydrogen, lower alkyl, lower alkoxy, halogen, lowerhalogenalkyl, lower halogenalkoxy and cyano;

R⁴ is selected from the group consisting of hydrogen, lower alkoxy,halogen, lower halogenalkyl, lower halogenalkoxy and cyano;

R⁷ and R^(7′) independently from each other are hydrogen or lower alkyl;and

R⁸ is a five- or six-membered heteroaryl group containing one, two orthree heteroatoms selected from the group consisting of N, O and S, saidheteroaryl group being unsubstituted or substituted by one or twosubstituents independently selected from the group consisting of loweralkyl, lower alkoxy, halogen, lower halogenalkyl and cycloalkyl;and pharmaceutically acceptable salts thereof.

One group of compounds according to the invention are those of formulaI, wherein one of A¹, A² or A³ is N and two of A¹, A² or A³ are CH.

Thus, the invention relates to pyridine compounds of formula I, whereinA¹ is N and A² and A³ are CH. A further group of compounds of thepresent invention are pyridine compounds of formula I, wherein A² is Nand A¹ and A³ are CH. The invention is also concerned with pyridinecompounds of formula I, wherein A³ is N and A¹ and A² are CH.

Another group of compounds of the present invention are those of formulaI, wherein two of A¹, A² or A³ are N and one of A¹, A² or A³ is CH.

The invention thus also relates to compounds of formula I, wherein A¹and A² are N and A³ is CH, i.e. to pyrimidine compounds of formula I.

A further group of compounds of the invention are those of formula I,wherein A² and A³ are N and A¹ is CH, i.e. to pyridazine compounds offormula I.

In addition, the invention relates to compounds of formula I, wherein A¹and A³ are N and A² is CH, i.e. to pyrazine compounds of formula I.

The invention relates to compounds of formula I, wherein R¹ is selectedfrom the group consisting of lower alkyl, cycloalkyl, lowercycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lowerhalogenalkyl, lower carbamoylalkyl, lower alkylcarbonylaminoalkyl, lowerphenylalkyl, lower heterocyclylalkyl wherein the heterocyclyl group isunsubstituted or substituted by oxo, lower heteroarylalkyl wherein theheteroaryl group is unsubstituted or mono- or di-substituted by loweralkyl, and phenyl which is unsubstituted or mono- or di-substituted byhalogen.

In particular, the invention relates to compounds of formula I, whereinR¹ is lower cycloalkylalkyl or lower halogenalkyl. More particularly, R¹is cyclopropylmethyl or lower halogenalkyl. Most particularly, R¹ isselected from the group consisting of cyclopropylmethyl,2,2,2-trifluoroethyl and 1,1,1-trifluoropropan-2-yl.

Compounds of formula I of the invention are those, wherein R² and R⁶ areindependently from each other hydrogen or halogen. Compounds of formulaI, wherein R² and R⁶ are hydrogen, are of particular interest.

The invention further relates to compounds of formula I, wherein R³ andR⁵ are independently from each other selected from the group consistingof hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl,lower halogenalkoxy and cyano. In particular, the invention relates tocompounds of formula I, wherein R³ and R⁵ are hydrogen.

Furthermore, the invention is concerned with compounds of formula I,wherein R⁴ is selected from the group consisting of hydrogen, loweralkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano. Moreparticularly, R⁴ is halogen. Most particularly, R⁴ is chloro.

The invention also relates to compounds of formula I, wherein R⁴ and R⁵together with the C atoms they are attached to form a five- orsix-membered carbocycle or a five- or six-membered heterocyclecontaining one, two or three heteroatoms selected from the groupconsisting of N, O and S, said carbocycle or heterocycle beingunsubstituted or substituted by one or two substituents independentlyselected from the group consisting of lower alkyl, lower alkoxy,halogen, lower halogenalkyl, lower halogenalkoxy and cyano. Inparticular, the invention relates to compounds of formula I, wherein R⁴and R⁵ together with the C atoms they are attached to form a five- orsix-membered carbocycle, more particularly a cycloalkyl ring such ascyclopentyl or cylohexyl. More particularly, the invention relates tocompounds of formula I wherein R⁴ and R⁵ together with the C atoms theyare attached to form a five- or six-membered heterocycle containing one,two or three heteroatoms selected from the group consisting of N, O andS, for example a [1,2,5]oxadiazolyl ring.

Compounds of formula I of the invention are further those, wherein R⁷and R^(7′) independently from each other are hydrogen or lower alkyl.More particularly, R⁷ and R^(7′) are hydrogen.

In addition, compounds of formula I of the present invention are those,wherein R⁸ is a five- or six-membered heteroaryl group containing one,two or three heteroatoms selected from the group consisting of N, O andS, said heteroaryl group being unsubstituted or substituted by one ortwo substituents independently selected from the group consisting oflower alkyl, lower alkoxy, halogen, lower halogenalkyl and cycloalkyl.In particular, the invention relates to compounds of formula I, whereinR⁸ is a five-membered heteroaryl group containing one, two or threeheteroatoms selected from the group consisting of N, O and S, saidheteroaryl group being unsubstituted or substituted by one or twosubstituents independently selected from the group consisting of loweralkyl, lower alkoxy, halogen, lower halogenalkyl and cycloalkyl.

More particularly, the invention relates to compounds of formula I,wherein R⁸ is a five-membered heteroaryl group is selected from thegroup consisting of oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and[1,2,4]oxadiazolyl, said heteroaryl group being unsubstituted orsubstituted by one or two substituents independently selected from thegroup consisting of lower alkyl, lower alkoxy, halogen, lowerhalogenalkyl and cycloalkyl. Most particularly, R⁸ is a five-memberedheteroaryl group selected from oxazolyl, isoxazolyl and[1,2,4]oxadiazolyl, said heteroaryl group being unsubstituted orsubstituted by one or two substituents independently selected from thegroup consisting of lower alkyl, lower alkoxy, halogen, lowerhalogenalkyl and cycloalkyl.

Particular compounds of formula I of the present invention are thefollowing:

-   4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic    acid (3-methoxy-isoxazol-5-ylmethyl)-amide,-   4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic    acid (3-isopropyl-isoxazol-5-ylmethyl)-amide,-   4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic    acid (3-ethyl-isoxazol-5-ylmethyl)-amide,-   4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic    acid (1-propyl-1H-pyrazol-3-ylmethyl)-amide,-   5-(4-chloro-phenyl)-N-(3-methoxy-isoxazol-5-ylmethyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide,-   4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic    acid (2-isopropyl-thiazol-4-ylmethyl)-amide,-   5-(4-chloro-phenyl)-N-(2-ethyl-thiazol-4-ylmethyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide,-   5-(4-chloro-phenyl)-N-(2-isopropyl-thiazol-4-ylmethyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide,-   5-(4-chloro-phenyl)-N-(2-propyl-thiazol-4-ylmethyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide,-   5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-(2-ethyl-thiazol-4-ylmethyl)-nicotinamide,-   5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-(2-propyl-thiazol-4-ylmethyl)-nicotinamide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-N-(5-trifluoromethyl-[1,2,4]oxadiazol-3-ylmethyl)-nicotinamide,-   4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic    acid (5-cyclopropyl-[1,2,4]oxadiazol-3-ylmethyl)-amide,-   5-(4-chloro-phenyl)-N-(1-propyl-1H-pyrazol-3-ylmethyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-N-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-nicotinamide,-   4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic    acid (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide,-   4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic    acid (3-cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-amide,-   4-(4-chlorophenyl)-5-(cyclopropylmethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)picolinamide,-   4-(4-chlorophenyl)-N-((5-methylisoxazol-3-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridazine-3-carboxylic    acid (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide,-   4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic    acid (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide,-   6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic    acid (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide.-   5-(4-chlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxamide,-   (S)-5-(4-chlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-6-(1,1,1-trifluoropropan-2-yloxy)pyridazine-3-carboxamide,-   4-(3,4-dichlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)pyrimidine-2-carboxamide,-   N-(4-chloro-1-methyl-1H-pyrazol-3-ylmethyl)-5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide,-   4-(4-chlorophenyl)-N-((5-isopropylisoxazol-3-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   4-(4-chlorophenyl)-N-((5-cyclopropylisoxazol-3-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   (S)-6-(4-chlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxamide,-   5-(4-chloro-phenyl)-N-(5-cyclopropyl-isoxazol-3-ylmethyl)-6-cyclopropylmethoxy-nicotinamide,-   5-(4-chlorophenyl)-N-((5-isopropylisoxazol-3-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide,-   5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-N-((5-isopropylisoxazol-3-yl)methyl)nicotinamide,-   4-(4-chlorophenyl)-N-((3-cyclopropylisoxazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   (S)-5-(4-chlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinamide,-   (S)-4-(4-chlorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxamide,-   (S)-6-(4-chlorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxamide,-   (S)-4-(4-chlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-5-(1,1,1-trifluoropropan-2-yloxy)picolinamide,-   (S)-5-(4-chlorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinamide,-   4-(4-chlorophenyl)-N-((5-isopropyl-1,2,4-oxadiazol-3-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   4-(4-chlorophenyl)-N-((3-isopropyl-1,2,4-oxadiazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic    acid (5-cyclopropyl-[1,2,4]oxadiazol-3-ylmethyl)-amide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic    acid (5-isopropyl-isoxazol-3-ylmethyl)-amide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic    acid (3-isopropyl-isoxazol-5-ylmethyl)-amide,-   4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic    acid (3-isopropyl-isoxazol-5-ylmethyl)-amide,-   4-(4-chlorophenyl)-5-(2,2,2-trifluoroethoxy)-N-((5-(trifluoromethyl)isoxazol-3-yl)methyl)picolinamide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic    acid (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide,-   6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic    acid (3-cyclopropyl-isoxazol-5-ylmethyl)-amide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic    acid (3-cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-amide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic    acid (3-cyclopropyl-isoxazol-5-ylmethyl)-amide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-N-(5-trifluoromethyl-isoxazol-3-ylmethyl)-nicotinamide,-   5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-(5-isopropyl-[1,2,4]oxadiazol-3-ylmethyl)-nicotinamide,-   6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid    (2-isopropyl-thiazol-4-ylmethyl)-amide,-   6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic    acid (5-isopropyl-isoxazol-3-ylmethyl)-amide,-   N-((2-tert-butylthiazol-4-yl)methyl)-4-(4-chlorophenyl)-5-(cyclopropylmethoxy)picolinamide,-   6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid    (5-isopropyl-isoxazol-3-ylmethyl)-amide,-   6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid    (2-cyclopropyl-oxazol-4-ylmethyl)-amide,-   6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid    (2-cyclopropyl-thiazol-4-ylmethyl)-amide,-   6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid    (5-trifluoromethyl-isoxazol-3-ylmethyl)-amide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-N-(3-trifluoromethyl-isoxazol-5-ylmethyl)-nicotinamide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic    acid (3-trifluoromethyl-isoxazol-5-ylmethyl)-amide,-   4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic    acid (3-trifluoromethyl-isoxazol-5-ylmethyl)-amide,-   4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic    acid (3-trifluoromethyl-isoxazol-5-ylmethyl)-amide,-   6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid    (2-tert-butyl-thiazol-4-ylmethyl)-amide,-   6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic    acid (3-isopropyl-isoxazol-5-ylmethyl)-amide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic    acid (2-tert-butyl-thiazol-4-ylmethyl)-amide,-   5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-(5-trifluoromethyl-isoxazol-3-ylmethyl)-nicotinamide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic    acid (5-trifluoromethyl-isoxazol-3-ylmethyl)-amide,-   (S)-4-(4-chlorophenyl)-N-((3-(trifluoromethyl)isoxazol-5-yl)methyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxamide,-   (S)-6-(4-chlorophenyl)-N-(pyridin-2-ylmethyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxamide,-   4-(4-chlorophenyl)-N-((2-cyclopropyloxazol-4-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   5-(4-chloro-3-methylphenyl)-N-((2-cyclopropylthiazol-4-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide,-   5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   4-(3-chloro-4-methylphenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   4-(4-chloro-3-methylphenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   4-(3,4-dimethylphenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   4-(4-chloro-3-methylphenyl)-N-((2-cyclopropylthiazol-4-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   4-(4-chloro-3-methylphenyl)-5-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)picolinamide,-   4-(3,4-dimethylphenyl)-5-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)picolinamide,-   5-p-tolyl-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(3-chloro-4-methylphenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(3-chloro-4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(4-ethylphenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(2,3-dihydro-1H-inden-5-yl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(4-chloro-3-fluorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide,-   5-(4-cyanophenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(4-chlorophenyl)-N-((1-(cyclopropylmethyl)-1H-pyrazol-3-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide,-   5-(3,4-difluorophenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(4-chlorophenyl)-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide,-   6-cyclobutoxy-5-(3,4-difluorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(4-chlorophenyl)-6-cyclobutoxy-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide-   5-(4-chloro-3-fluorophenyl)-6-cyclobutoxy-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(4-chloro-3-methylphenyl)-6-cyclobutoxy-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   6-(cyclopropylmethoxy)-5-(3,4-difluorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(3,4-difluorophenyl)-6-(2-methoxyethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(4-chloro-3-fluorophenyl)-6-(2-methoxyethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(4-chloro-3-methylphenyl)-6-(2-methoxyethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(3,4-difluorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide,-   5-benzo[1,2,5]oxadiazol-5-yl-6-(2,2,2-trifluoro-ethoxy)-N-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-nicotinamide,-   5-(4-chlorophenyl)-6-cyclobutoxy-N-(pyridin-2-ylmethyl)nicotinamide,-   5-(4-chlorophenyl)-6-(2-hydroxyethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   (R)-5-(4-chlorophenyl)-6-(tetrahydrofuran-3-yloxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   (SR)-5-(4-chlorophenyl)-6-((tetrahydrofuran-3-yl)methoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,    and-   (RS)-5-(4-chloro-phenyl)-6-[(R)-1-(tetrahydro-furan-3-yl)methoxy]-N-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-nicotinamide,    or pharmaceutically acceptable salts thereof.

Particularly advantageous compounds of formula I of the presentinvention are the following:

-   4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic    acid (3-methoxy-isoxazol-5-ylmethyl)-amide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-N-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-nicotinamide,-   6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic    acid (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide,-   5-(4-chlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxamide,-   4-(4-chlorophenyl)-N-((5-cyclopropylisoxazol-3-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   (S)-6-(4-chlorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxamide,-   (S)-5-(4-chlorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinamide,-   4-(4-chlorophenyl)-N-((3-isopropyl-1,2,4-oxadiazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic    acid (3-cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-amide, and-   6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic    acid (3-isopropyl-isoxazol-5-ylmethyl)-amide,-   5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic    acid (5-trifluoromethyl-isoxazol-3-ylmethyl)-amide,-   4-(4-chlorophenyl)-N-((2-cyclopropyloxazol-4-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide,-   5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(3-chloro-4-methylphenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(3-chloro-4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(3,4-difluorophenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   6-cyclobutoxy-5-(3,4-difluorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(4-chloro-3-fluorophenyl)-6-cyclobutoxy-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(4-chloro-3-methylphenyl)-6-cyclobutoxy-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,-   5-(3,4-difluorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide,-   5-benzo[1,2,5]oxadiazol-5-yl-6-(2,2,2-trifluoro-ethoxy)-N-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-nicotinamide,    and-   5-(4-chlorophenyl)-6-(2-hydroxyethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide,    or pharmaceutically acceptable salts thereof.

The compounds of formula I can be prepared by a process, which processcomprises coupling a compound of formula

wherein A¹, A², A³ and R¹ to R⁶ are as defined herein before, with anamine of the formula

wherein R⁷, R^(7′) and R⁸ are as defined herein before, with the help ofa coupling agent under basic conditions,and, if desired, converting the resulting compound of formula I into apharmaceutically acceptable salt thereof.

Coupling agents for the reaction of compounds of formula II with aminesof formula III are for example N,N′-carbonyldiimidazole (CDI),N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU). In particular, the coupling agent is TBTU. Suitable basesinclude triethylamine, diisopropylethylamine and, preferably, Hünig'sbase. Alternative methods known in the art may commence by preparing theacid chloride from II and coupling with an amine of formula III in thepresence of a suitable base.

The synthesis of the compounds with the general structure I can beaccomplished according to the following schemes.

Following the procedure according to scheme 1, compound AA(6-chloro-5-hydroxy-4-iodo-2-pyridinemethanol, CAN 208519-37-3) can beused as starting material. AA is commercially available or canalternatively be prepared by a two step sequence from2-chloro-3-pyridinol following literature procedures.

Compound AB can be prepared from AA by reaction with a suitablysubstituted primary or secondary alkylhalide R¹—X or primary orsecondary alkyltrifluoromethanesulfonate R¹-OTf in the presence of abase, for example sodium hydride, in a inert solvent, for examplehexamethylphosphoramide, at temperatures from room temperature to refluxtemperature of the solvent, preferably at elevated temperature e.g. 120°C.

Compound AC can be prepared from AB by coupling a suitably substitutedaryl metal species of formula AF, preferably an arylboronic acid orarylboronic acid ester, with AB in the presence of a suitable catalyst,preferably a palladium catalyst and more preferablypalladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene)complexes and a base, preferably triethylamine or sodium carbonate in aninert solvent such as dimethylformamide or toluene.

Compound AD can be obtained by selective hydrogenation of compound AC bymethods known in the art, for example by hydrogenation with zinc inacetic acid in the presence of tetramethylammonium bromide attemperatures from room temperature to reflux temperature of the solvent,preferably at a temperature of 50° C.

Compound II-a can be prepared from AD by oxidation using the vast arrayof possibilities known in the art. A convenient method is the use of aTEMPO catalyzed oxidation with a sodiumchlorite-sodiumhypochloritemixture in a suitable solvent mixture, preferably inacetonitrile/phosphate buffer mixtures, at temperatures from roomtemperature to elevated temperatures, preferably at 35° C.

Compound I-a can be prepared from II-a and the corresponding amine offormula III by suitable amide bond forming reactions. These reactionsare known in the art. For example coupling reagents likeN,N′-carbonyl-diimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) can be employed to affect such transformations. A convenientmethod is to use for example TBTU and a base, for example Hünig's base(N-ethyldiisopropylamine) in an inert solvent such as for exampledimethylformamide at room temperature.

Following the procedure according to scheme 2, compound BA(5-bromo-6-chloro-3-pyridinecarboxylic acid methylester, CAN 78686-77)can be used as starting material. BA is commercially available or canalternatively be prepared by a multi step sequence from6-hydroxy-3-pyridinecarboxylic acid following literature procedures.

Compound BB can be prepared from BA by coupling a suitably substitutedaryl metal species of formula AF, preferably a arylboronic acid orarylboronic acid ester, with BA in the presence of a suitable catalyst,preferably a palladium catalyst and more preferablypalladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene)complexes and a base, preferably triethylamine or sodium carbonate in aninert solvent such as dimethylformamide or toluene.

Compound BC can be obtained by saponification of compound BB by methodsknown in the art, for example by saponification with an alkalimetalhydroxide, for example lithium hydroxide, in a suitable solvent, forexample a mixture of THF and water.

Compound II-b can be prepared from BC by reaction with a suitablysubstituted primary or secondary alcohol R¹—OH in the presence of abase, for example potassium hydroxide, in a inert solvent, for exampledimethylsulfoxide, at temperatures from room temperature to refluxtemperature of the solvent, preferably at room temperature.

Compound I-b can be prepared from II-b and the corresponding amine offormula III by suitable amide bond forming reactions. These reactionsare known in the art. For example coupling reagents likeN,N′-carbonyl-diimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) can be employed to affect such transformations. A convenientmethod is to use for example TBTU and a base, for example Hünig's base(N-ethyldiisopropylamine) in an inert solvent such as for exampledimethylformamide at room temperature.

Following the procedure according to scheme 3 compound CA(2,6-dichloro-3-fluoro-pyridine CAN 52208-50-1) can be used as startingmaterial. CA is commercially available.

Compounds of the general formula CB can be prepared from compound CA bycoupling a suitably substituted aryl metal species of the generalformula AF, preferably an arylboronic acid or arylboronic acid ester,with compounds of the general formula CA in the presence of a suitablecatalyst, preferably a palladium catalyst and more preferablypalladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino) ferrocene)complexes and a base, preferably triethylamine or sodium carbonate in aninert solvent such as dimethylformamide, toluene, tetrahydrofuran, wateror acetonitrile preferably tetrahydrofuran and mixtures oftetrahydrofuran and water.

Compounds of the general formula CC can be obtained from compounds ofthe general formula CB by reaction with an alcohol of the generalformula R³OH more specifically with 2,2,2-trifluoroethanol andcyclopropylmethanol in the presence of a suitable base such as sodiumhydroxide, sodium hydride and cesium carbonate in an inert solvent suchas tetrahydrofuran, dimethylformamide or dimethylsulfoxide, inparticular dimethylsulfoxide, at a temperature between −20° C. toreflux, preferably at room temperature.

Compounds of the general formula II-c can be obtained from compounds ofthe general formula CC by transition metal catalyzed, more specificallypalladium catalyzed, preferentially palladium(II)chloride-dppf catalyzedreaction with carbon monoxide in a suitable solvent such as a primaryalcohol, particularly methanol, at pressures of carbon monoxide of 1 to200 bar, in particular 1 to 70 bar and temperatures of 0 to 150° C.,particularly 1 to 100° C. followed by saponification of the resultingester by methods well known to the ones skilled in the art.

Compounds of the general formula I-c can be prepared from compounds ofthe general formula II-c and the corresponding amine of the generalformula III by suitable amide bond forming reactions described above.

Following the procedure according to scheme 4 certain compounds of thegeneral formula DA (e.g. 3-chloro-6-methoxy-pyridazine, CAN 1722-10-7)are commercially available and can be used as starting materials.Alternatively, compounds of the general formula DA can be obtained from3,6-dichloro-pyridazine (CAN 141-30-0) by reaction with an alcohol ofthe general formula R¹OH more specifically with cyclopropylmethanol inthe presence of a suitable base such as sodium hydroxide, sodium hydrideand cesium carbonate in an inert solvent such as tetrahydrofuran,dimethylformamide or dimethylsulfoxide, particularly dimethylsulfoxide,at temperatures between −20° C. to reflux, in particular at roomtemperature.

Compounds of the general formula DB can be obtained from compounds ofthe general formula DA by ortho directed metalation using a suitablebase such as LDA or lithium 2,2,6,6-tetramethylpiperidide in an inertsolvent such as tetrahydrofuran at low temperatures, particularly −110°C. to −78° C. followed by reaction with iodine at low temperatures,particularly at −110° C. to −78° C.

Compounds of the general formula DC can be obtained by coupling asuitably substituted aryl metal species of the general formula AF,preferably an arylboronic acid or arylboronic acid ester, with compoundsof the general formula DB in the presence of a suitable catalyst,preferably a palladium catalyst and more preferablypalladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene)complexes and a base, particularly triethylamine or sodium carbonate inan inert solvent such as dimethylformamide, toluene, tetrahydrofuran oracetonitrile, in particular tetrahydrofuran.

Compounds of the general formula II-d can be obtained from compounds ofthe general formula DC by palladium acetate catalyzed reaction withcarbon monoxide in a suitable solvent such as a primary alcohol,particularly methanol, at pressures of carbon monoxide of 1 to 200 bar,particularly 1 to 70 bar and temperatures of 0° C. to 150° C., inparticular 1° C. to 100° C. followed by saponification of the resultingester by methods well known to the ones skilled in the art.

Ether side chains R¹O that are incompatible with the above describedortho directed metallation protocol, such as trifluoroethyl ethers canalternatively be introduced according to scheme 4 by reactions ofcompounds with the formula DC, in which R¹ represents a simple alkylgroup such as methyl or cyclopropylmethyl, with suitable acids such ashydrochloric acid in an inert solvent such as dioxane to yield compoundsof the general formula DD.

Compounds of the general formula DE can be obtained from compounds ofthe general formula DD by Pd catalyzed, preferentially PdCl₂.dppfcatalyzed reaction with carbon monoxide in a suitable solvent such as aprimary alcohol, particularly methanol, at pressures of carbon monoxideof 1 to 200 bar, in particular 1 to 70 bar and temperatures of 0° C. to150° C., particularly 0 to 120° C.

Compounds of the general formula DF can be obtained from compounds ofthe general formula DE by reaction with a chlorinating agent such asphosphoroxychloride in a suitable solvent or neat at temperaturesranging from room temperature to reflux.

Compounds of the general formula II-d can be obtained from compounds ofthe general formula DF by reaction with an alcohol of the generalformula R¹OH, more specifically with 2,2,2-trifluoroethanol, in thepresence of a suitable base such cesium carbonate in an inert solventsuch as 2,2,2-trifluoroethanol, tetrahydrofuran, dimethylformamide ordimethylsulfoxide, particularly dimethylsulfoxide, at temperaturesbetween −20° C. to reflux, in particular at room temperature, followedby saponification of the resulting ester by methods well known to theones skilled in the art.

Compounds of the general formula I-d can be prepared from compounds ofthe general formula II-d and the corresponding amine of the generalformula III by suitable amide bond forming reactions described above.

Following the procedure according to scheme5,2,4-dichloro-5-fluoro-pyrimidine (CAS RN 2927-71-1) can be used asstarting material for the preparation of compounds of the generalformula EA by coupling with a suitably substituted aryl metal species ofthe general formula AF, particularly an arylboronic acid or arylboronicacid ester in the presence of a suitable catalyst, in particular apalladium catalyst and more particularlypalladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene)complexes and a base such as triethylamine or sodium carbonate in aninert solvent such as dimethylformamide, toluene, tetrahydrofuran oracetonitrile, particularly in mixtures of tetrahydrofuran and water.

Compounds of the general formula EB can be obtained from compounds ofthe general formula EA by reaction with an alcohol of the generalformula R¹OH more specifically with 2,2,2-trifluoroethanol andcyclopropylmethanol in the presence of a suitable base such as sodiumhydroxide, sodium hydride and cesium carbonate in an inert solvent suchas tetrahydrofuran, dimethylformamide or dimethylsulfoxide, particularlydimethylsulfoxide, at temperatures between −20° C. to reflux, inparticular at room temperature.

Compounds of the general formula II-e can be obtained from compounds ofthe general formula EB by palladium (preferentially PdCl₂.dppf)catalyzed reaction with carbon monoxide in a suitable solvent such as aprimary alcohol, particularly methanol, at pressures of carbon monoxideof 1 to 200 bar, particularly 1 to 70 bar and temperatures of 0 to 150°C., particularly 0° C. to 120° C., followed by saponification of theresulting ester by methods well known to the ones skilled in the art.

Compounds of the general formula I-e can be prepared from compounds ofthe general formula II-e and the corresponding amine of the generalformula III by suitable amide bond forming reactions described above.

Following the procedure according to scheme 6 compounds of the generalformula IIf can be obtained from compound F (CAN960247-79-4,2-pyrazinecarboxylic acid, 5-bromo-6-(4-chlorophenyl)-,methyl ester) by reaction with an alcohol of the general formula R¹OH,more specifically with 2,2,2-trifluoroethanol,(S)-1,1,1-trifluoro-propan-2-ol and cyclopropylmethanol in the presenceof a suitable base such as sodium hydroxide, sodium hydride and cesiumcarbonate in an inert solvent such as tetrahydrofuran, dimethylformamideor dimethylsulfoxide, particularly dimethylsulfoxide, at temperaturesbetween −20° C. to reflux, in particular at room temperature.

As described above, the compounds of formula I of the present invention,or pharmaceutically acceptable salts thereof, can be used as medicamentsfor the treatment and/or prophylaxis of diseases which can be treatedwith HDL-cholesterol raising agents. Examples of such diseases areatherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, cardiovascular diseases such as angina, ischemia,cardiac ischemia, stroke, myocardial infarction, reperfusion injury,angioplastic restenosis, hypertension, and vascular complications ofdiabetes, obesity or endotoxemia. The use as medicament for thetreatment and/or prevention of dyslipidemia, atherosclerosis andcardiovascular diseases is of particular interest.

The invention therefore also relates to pharmaceutical compositionscomprising a compound of formula I as defined above, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier and/or adjuvant. The pharmaceutical compositions areuseful in the treatment and/or prophylaxis of diseases which can betreated with HDL-cholesterol raising agents.

Thus, the invention relates to a pharmaceutical composition as definedabove for use in the treatment and/or prophylaxis of atherosclerosis,peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial hypercholesterolemia, cardiovascular diseases such as angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, and vascularcomplications of diabetes, obesity or endotoxemia.

In another embodiment, the invention relates to a method for thetreatment and/or prophylaxis of diseases which can be treated withHDL-cholesterol raising agents, which method comprises administering atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, to a patient in need thereof.Examples of such diseases are atherosclerosis, peripheral vasculardisease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial hypercholesterolemia, cardiovascular diseases such as angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, and vascularcomplications of diabetes, obesity or endotoxemia. A method for thetreatment and/or prophylaxis of dyslipidemia, atherosclerosis andcardiovascular diseases is preferred.

The invention also relates to the compounds of formula I, orpharmaceutically acceptable salts thereof, for use as medicaments. Morespecifically, the invention relates to compounds of formula I, orpharmaceutically acceptable salts thereof, for use as HDL-cholesterolraising agents. Thus, the invention is concerned with compounds offormula I, or pharmaceutically acceptable salts thereof, for use in thetreatment and/or prophylaxis of atherosclerosis, peripheral vasculardisease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial hypercholesterolemia, cardiovascular diseases such as angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, and vascularcomplications of diabetes, obesity or endotoxemia, in particular for usein the treatment and/or prophylaxis of dyslipidemia, atherosclerosis andcardiovascular diseases.

In addition, the invention relates to the use of compounds of formula Ias defined above, or pharmaceutically acceptable salts thereof, for thepreparation of a medicament for the treatment and/or prophylaxis ofdiseases can be treated with HDL raising agents. Examples of suchdiseases are atherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, cardiovascular diseases such as angina, ischemia,cardiac ischemia, stroke, myocardial infarction, reperfusion injury,angioplastic restenosis, hypertension, and vascular complications ofdiabetes, obesity or endotoxemia. The use of compounds of formula I asdefined above, or pharmaceutically acceptable salts thereof, for thepreparation of medicaments for the treatment and/or prophylaxis ofdyslipidemia, atherosclerosis and cardiovascular diseases is ofparticular interest.

In addition, HDL raising agents of formula I, or pharmaceuticallyacceptable salts thereof, are useful in combination or association withanother compound, said compound being selected from the group consistingof an HMG-CoA reductase inhibitor, an microsomal triglyceride transferprotein (MTP)/ApoB secretion inhibitor, a PPAR activator, a cholesterylester transfer protein (CETP) inhibitor, a bile acid reuptake inhibitor,a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, afibrate, niacin, a preparation containing niacin or other HM74aagonists, an ion-exchange resin, an antioxidant, an ACAT inhibitor or abile acid sequestrant.

The invention therefore also relates to pharmaceutical compositionscomprising a compound of formula I as defined above, or apharmaceutically acceptable salt thereof, in combination or associationwith a compound selected from the group consisting of an HMG-CoAreductase inhibitor, an microsomal triglyceride transfer protein(MTP)/ApoB secretion inhibitor, a PPAR activator, a cholesteryl estertransfer protein (CETP) inhibitor, a bile acid reuptake inhibitor, acholesterol absorption inhibitor, a cholesterol synthesis inhibitor, afibrate, niacin, a preparation containing niacin or other HM74aagonists, an ion-exchange resin, an antioxidant, an ACAT inhibitor or abile acid sequestrant, as well as a pharmaceutically acceptable carrierand/or adjuvant.

The invention further relates to compounds of formula I as definedabove, or pharmaceutically acceptable salts thereof, in combination orassociation with a compound selected from the group consisting of anHMG-CoA reductase inhibitor, an microsomal triglyceride transfer protein(MTP)/ApoB secretion inhibitor, a PPAR activator, a cholesteryl estertransfer protein (CETP) inhibitor, a bile acid reuptake inhibitor, acholesterol absorption inhibitor, a cholesterol synthesis inhibitor, afibrate, niacin, a preparation containing niacin or other HM74aagonists, an ion-exchange resin, an antioxidant, an ACAT inhibitor or abile acid sequestrant for use in the treatment and/or prophylaxis ofdiseases such as atherosclerosis, peripheral vascular disease,dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, cardiovascular disorders, angina, ischemia,cardiac ischemia, stroke, myocardial infarction, reperfusion injury,angioplastic restenosis, hypertension, and vascular complications ofdiabetes, obesity or endotoxemia.

The invention also relates to a method for the treatment and/orprophylaxis of diseases which can be treated with HDL-cholesterolraising agents, which method comprises administration of atherapeutically effective amount of a compound according to formula I,or a pharmaceutically acceptable salt thereof, in combination orassociation with a therapeutically effective amount of a compoundselected from the group consisting of an HMG-CoA reductase inhibitor, anmicrosomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor,a PPAR activator, a cholesteryl ester transfer protein (CETP) inhibitor,a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, acholesterol synthesis inhibitor, a fibrate, niacin, a preparationcontaining niacin or other HM74a agonists, an ion-exchange resin, anantioxidant, an ACAT inhibitor or a bile acid sequestrant.

Pharmaceutical Compositions

The compounds of formula I and/or their pharmaceutically acceptablesalts can be used in the form of pharmaceutical compositions forenteral, parenteral or topical administration. They can be administered,for example, perorally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatine capsules, solutions, emulsions orsuspensions, orally, e.g. in the form of buccal cavities, rectally, e.g.in the form of suppositories, parenterally, e.g. in the form ofinjection solutions or infusion solutions for intramuscular, intravenousor subcutaneous injection, or topically, e.g. in the form of ointments,creams or oils. Oral administration is of particular interest.

The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and/or theirpharmaceutically acceptable salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers might,however, be required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavor-improving agents, salts for varyingthe osmotic pressure, buffer substances, solubilizers, colorants andmasking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The therapeutically effective amount or dosage of the compounds offormula I can vary within wide limits depending on the disease to becontrolled, the age and the individual condition of the patient and themode of administration, and will, of course, be fitted to the individualrequirements in each particular case. For adult patients a daily dosageof about 1 to 100 mg, especially about 1 to 50 mg, comes intoconsideration. Depending on severity of the disease and the precisepharmacokinetic profile the compound could be administered with one orseveral daily dosage units, e.g. in 1 to 3 dosage units.

The pharmaceutical compositions conveniently contain about 1-100 mg,preferably 5-50 mg, of a compound of formula I.

The following examples C1 to C3 illustrate typical compositions of thepresent invention, but serve merely as representative thereof.

Example C1

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mgMicrocrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg FilmCoat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mgTitan dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is then mixed with sodiumstarch glycolate and magnesium stearate and compressed to yield kernelsof 120 or 350 mg respectively. The kernels are lacquered with an aq.solution/suspension of the above mentioned film coat.

Example C2

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mgMaize starch 20.0 mg Talc 5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C3

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Aceticacid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of Polyethylene glycol400 and water for injection (part). The pH is adjusted to 5.0 byaddition of acetic acid. The volume is adjusted to 1.0 ml by addition ofthe residual amount of water. The solution is filtered, filled intovials using an appropriate overage and sterilized.

Pharmacological Tests

The following tests were carried out in order to determine the activityof the compounds of formula I and their valuable pharmacologicalproperties.

Detection of Upregulation of ABCA1 Protein in Cells

The ability of compounds of the invention to increase the level of ABCA1protein is determined in replicate cultures of THP-1 macrophage cells in96-well microplates. Cells are plated at an initial density of 100,000cells/well in 100 μl medium and differentiated to adherent macrophageswith the addition of PMA (100 nM) for 68 hrs in 10% fetal bovine serum,3 μl/L of b-mercaptoethanol, RPMI-1640 medium. Then, cells are incubatedwith RPMI-1640 medium containing 1% FCS, 25 μg/ml acetylated LDL, for 24hours at 37°. Following incubation with acetylated LDL, cells are washedtwice with 50 μl PBS and incubated with 100 μl of RPMI-1640 mediumcontaining the compound of interest solubilized in DMSO for anadditional 24 hrs. The final DMSO concentration in presence of cells ismaintained at 0.5%. ApoA-I binding assay using High Content ImageAnalysis is initiated by replacing with fresh medium, RPMI withoutPhenol Red, 0.2% BSA containing AlexaFluor®647 labeled ApoA-I for 2h/37° C./5% CO2. Then, cells are fixed with 4% Formaldehyde in PBS (15min, RT). Following Nuclei are stained with Hoechst solution (3 μM PBS)and Cytoplasm with Cell Mask Blue (2 μg/ml PBS), 15 min, RT. Finally thestained cells are fixed with a second round of formaldehyde treatment.Fixed stained cells are washed and kept in PBS at 4° C. and can be readimmediately until one month after preparation. That the binding ofApoA-I indeed reflected the level of ABCA1 in the cell, was demonstratedby loss of signal when ABCA1 expression was artificially reduced bytransfection with small interfering RNA's.

The Alexa Fluor 647-labeled Apolipoprotein A-I (20 nM) was prepared asfollows: Human recombinant Apolipoprotein A-I (ApoA-I) was exchanged toa buffer of 0.02 M NaHCO₃ at pH 8.2 on an NAP desalting column (GEHealthcare) and brought to a concentration to 40 μM (1.13 mg/ml) byadjustment with the same buffer. The ApoA-I was fluorescently labeled byincubation with Alexa Fluor carboxylic acid succimidyl ester. (AlexaFluor 647, Invitrogen A-20006) at a 2:1 molar ratio (Alexa to ApoA-I)for 1 h under shaking at RT. The remaining unconjugated label wasremoved by buffer exchange to 0.02M NaHCO₃ at pH 8.2.

Imaging and data collection were performed on an OPERA confocalmicroplate imaging reader using a 20× water immersion objective andUV360 or 405 laser to identify the cell nuclei and a 635 laser toidentify the fluorescent ApoA-I. Eight fields of view are captured perwell. Image capture and analysis was performed with the Acapellasoftware. Background fluorescence detected in control wells withoutApoA-I was subtracted.

Using XLfit3 program (ID Business Solutions Ltd. UK), the model 205 forDose Response One Site is used to calculate the EC₅₀ values. Thecompounds of the present invention exhibit EC₅₀ values in a range of 0.1μM to 10 μM in the ABCA1 protein detection assay. Preferably, thecompounds of the present invention have EC₅₀ values in a range of 0.1 μMto 3 μM.

TABLE 1 ABCA1 protein increasing efficacy Example EC₅₀ [μM] 1 2.01 21.09 3 1.24 4 2.8 5 2.1 6 7.8 7 1.5 8 0.9 9 0.9 11 1.5 12 1.18 14 0.9515 0.84 18 6.91 22 2.27 23 0.93 25 1.47 27 0.97 28 0.87 29 1.87 31 0.5334 0.77 38 0.95 42 0.8 44 1.02 46 0.78 48 0.73 60 0.75 61 0.82 64 0.8667 0.78 70 1.56 71 4.29 72 0.5 74 1.3 76 1.64 77 0.33 79 1.17 80 3.13 810.89 89 1.96 91 0.62 94 0.31 99 1.25 100 0.58Cholesterol Efflux Assay

The ability of compounds of the invention to stimulate cholesterolefflux is determined in replicate cultures of THP-1 cells in 96-wellmicroplates. Cells are plated at an initial density of 150,000cells/well and differentiated to macrophages with the addition of PMA(100 ng/ml) for 72 hrs in 10% fetal bovine serum, 3 μl/L ofb-mercaptoethanol, RPMI-1640 medium. Cells are washed once withRPMI-1640 and loaded with RPMI-1640 medium containing 2% FCS, 50 μg/mlacetylated LDL, and 10 μCi/ml [³H]cholesterol for 48 hours at 37° C.After loading the cells are washed once with RPMI-1640 and incubatedwith the compound of interest from DMSO solutions for an additional 24hrs in RPMI-1640 medium containing 1 mg/ml fatty acid free-bovine serumalbumin (BSA). Upon incubation cells are washed once, and cholesterolefflux is induced by the addition of 10 μg/ml Apolipoprotein AI inRPMI-1640 containing 1 mg/ml BSA and in the presence of the compound foran additional 6 hrs. Following incubation radioactivity is determined inthe supernatants and cholesterol efflux is expressed as the percentstimulation over replicate cultures treated only with DMSO. Sigmoidalcurves were fitted using the XLfit3 program (ID Business Solutions Ltd.UK) and EC₅₀ values were determined.

The compounds of the present invention exhibit EC₅₀ values in a range of0.1 μM to 3.0 μM in the cholesterol efflux assay. Preferably, thecompounds of the present invention have EC₅₀ values in a range of 0.1 μMto 1.5 μM.

CB1 and CB2 Receptor Affinity

The affinity of the compounds of the invention for cannabinoid receptorswas determined using membrane preparations of human embryonic kidney(HEK) cells in which the human CB1 receptor is transiently transfectedusing a Semliki Forest Virus system in conjunction with [3H]-CP-55,940as radioligand. After incubation of freshly prepared cell membranepreparation with the [³H]-ligand, with or without addition of compoundsof the invention, separation of bound and free ligand was performed byfiltration over glass fiber filters. Radioactivity on the filter wasmeasured by scintillation counting.

The affinity of the compounds of the invention for cannabinoid CB2receptors was determined using membrane preparations of human embryonickidney (HEK) cells in which the human CB2 receptor is transientlytransfected using a Semliki Forest Virus system in conjunction with[³H]-CP-55,940 as radioligand. After incubation of freshly prepared cellmembrane preparation with the [³H]-ligand, with or without addition ofcompounds of the invention, separation of bound and free ligand wasperformed by filtration over glass fiber filters. Radioactivity on thefilter was measured by scintillation counting.

The ability of the compounds to displace the radioligand [³H]-CP-55,940was measured at a concentration of 10 μM and values provided as [%inhibition @ 10 μM] both for the CB 1 and CB2 receptor assay, The lower% inhibition is, the lower the likelihood of side effects based on CB1or CB2 receptor inhibition is.

The compounds of the present invention exhibit values below 50%inhibition in both the CB1 and CB2 receptor assay at a concentration of10 μM. Preferably, the compounds of the present invention exhibit valuesbelow 35% inhibition in both the CB1 and CB2 receptor assays and evenmore preferably below 20% in both assays.

TABLE 2 CB1 and CB2-receptor affinity CB1 receptor affinity CB2 receptoraffinity Example [% inhibition @ 10 μM] [% inhibition @ 10 μM] 1 32 28 230 14 3 38 18 4 26 33 5 48 5 6 5 15 7 22 6 8 24 10 9 18 1 10 28 28 11 2512 12 43 −4 13 35 46 14 48 12 15 45 −6 16 38 15 17 48 45 18 28 24 19 3043 20 33 34 21 44 35 22 40 6 23 18 7 24 39 16 25 11 17 26 40 22 27 40 2428 42 29 29 27 17 30 48 38 31 47 11 32 47 26 33 33 26 34 33 14 35 50 2236 36 14 37 40 20 38 32 −2 39 26 21 40 29 19 41 23 19 42 34 13 43 37 1444 29 8 45 37 −2 46 30 0 47 46 16 48 35 19 49 36 13 50 38 −5 51 47 2 5238 43 53 43 23 54 20 12 55 44 33 56 38 32 57 31 36 58 42 19 59 49 -2 6030 -3 61 32 17 62 44 24 63 36 38 64 33 7 65 18 missing 66 49 18 67 25 368 45 3 69 34 40 70 28 14 71 2 −7 72 34 −1 73 22 45 74 11 22 75 19 34 768 9 77 4 11 78 17 5 79 42 4 80 15 −4 81 4 7 82 30 27 83 44 −2 84 49 2185 7 8 86 37 9 87 45 3 88 48 11 89 28 4 90 50 14 91 23 12 92 43 9 93 187 94 19 2 95 39 21 96 45 8 97 48 25 98 41 16 99 20 9 100 15 8 101 45 37102 26 −4 103 47 24 104 39 9 105 47 17

Further demonstration of biological activities of the compounds of thepresent invention may be accomplished through the following in vivoassays that are well known in the art.

Effects on Plasma Lipid Levels in Lean, Chow Fed Rats

The effects of compounds of compounds of formula I on plasma lipidlevels were determined in lean, chow-fed Sprague-Dawley rats withcompounds administered by p.o. gavage. After one week of acclimation,blood samples were collected from 4 hour-fasted animals for plasma lipiddetermination. Animals were then assigned to treatment groups based onHDL-cholesterol levels. Compounds of formula I were administered bygavage, once daily for five days. Control animals received vehiclealone. Blood was collected on day five from 4 hour-fasted rats, 2 hoursafter a final treatment, for plasma lipid analysis. Total cholesterol,HDL-cholesterol, and triglycerides were determined by measuring totalcholesterol, HDL-cholesterol, and triglyceride using colorimetricenzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). HDL-C wasalso quantified using size exclusion chromatography on superpose-6column using a SMART system (Pharmacia). Lipoprotein distribution wascalculated assuming a Gaussian distribution for each peak, using anonlinear, least-squares curve-fitting procedure to calculate the areaunder the curve. Compound concentration was also determined in plasma.

Effects on Plasma Lipid Levels in Obese, High Fat Diet Fed Rats

Efficacy of compounds in modulating plasma lipid levels was determinedalso in obese male Sprague Dawley rats after 28-29 days administrationof compounds. Male Sprague-Dawley rats of 10 weeks of age were fed ahigh fat diet during 3 weeks. Obese rats were distributed in groupsaccording to homogeneous BW and FI evaluated a week before the start ofthe treatment. Treatment was administered as food-Admix. On day 29,blood was taken in the morning under slight anesthesia (retro-orbitalmethod) in post-prandial conditions i.e. 4 h after food was removed.Plasma was separated from blood by low speed centrifugation and selectedorgans were taken (e.g liver, fat). Total cholesterol, HDL-cholesterol,and triglycerides were determined by measuring total cholesterol,HDL-cholesterol, LDL-cholesterol and triglyceride using colorimetricenzymatic assays (Roche Diagnostic GmbH, Mannheim, Germany). HDL-C wasalso quantified using size exclusion chromatography on superpose-6column using a SMART system (Pharmacia). Lipoprotein distribution wascalculated assuming a Gaussian distribution for each peak, using anonlinear, least-squares curve-fitting procedure to calculate the areaunder the curve. Compound concentration was also determined in plasma.

Effects on Plasma Lipid Levels in Hamsters

Efficacy of compounds in modulating plasma lipid levels was determinedin hamsters after 5 days of daily administration of compounds. Malehamsters of 6-8 weeks of age were used in the studies. After one week ofacclimation, blood samples were collected from 4 hour-fasted animals forplasma lipid determination. Animals were then assigned to treatmentgroups based on HDL-cholesterol levels. Compounds were administered bygavage, once daily for five days. Control animals received vehiclealone. Blood was collected on day five from 4 hour-fasted hamsters, 2hours after a final treatment, for plasma lipid analysis. Totalcholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides weredetermined using colorimetric enzymatic assays (Roche Diagnostic GmbH,Mannheim, Germany). HDL-cholesterol, LDL-cholesterol, andVLDL-cholesterol levels were also quantified using size exclusionchromatography on superpose-6 column using a SMART system (Pharmacia).Lipoprotein distribution was calculated assuming a Gaussian distributionfor each peak, using a nonlinear, least-squares curve-fitting procedureto calculate the area under the curve. Compound concentration was alsodetermined in plasma.

Effects on Plasma Lipid Levels in Cholesterol/Fat Fed Hamsters

Efficacy of compounds in modulating plasma lipid levels was determinedin hamsters after 5 days of daily administration of compounds. Malehamsters of 6-8 weeks of age were used in the studies. After one week ofacclimation, blood samples were collected from 4 hour-fasted animals forplasma lipid determination. Animals were then assigned to treatmentgroups based on HDL-cholesterol levels. Compounds were administered bygavage, once daily for five days. Control animals received vehiclealone. Blood was collected on day five from 4 hour-fasted hamsters, 2hours after a final treatment, for plasma lipid analysis. Totalcholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides weredetermined using colorimetric enzymatic assays (Roche Diagnostic GmbH,Mannheim, Germany). HDL-cholesterol was also determined after selectiveprecipitation of HDL from plasma by standard procedures.

EXAMPLES

MS=mass spectrometry; EI=electron ionization; ESI=electrospray; NMR dataare reported in parts per million (δ) relative to internaltetramethylsilane and are referenced to the deuterium lock signal fromthe sample solvent (d₆-DMSO unless otherwise stated); coupling constants(J) are in Hertz, mp=melting point; bp=boiling point; HPLC=LC=highperformance liquid chromatography, Rt=retention time, TLC=thin layerchromatography, RT=room temperature,TBTU=O-(Benzotriazol-1-yl)-N,N′,N′-tetramethyl-uronium-tetrafluoroborate;TEMPO=2,2,6,6-tetra-methylpiperidine 1-oxyl radical,DMF=dimethylformamide, DMSO=dimethyl-sulfoxide, THF=tetrahydrofuran,CAN=CAS Registry Number.

Preparation of Intermediates Example A Preparation of[6-chloro-4-iodo-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol

6-Chloro-5-hydroxy-4-iodo-2-pyridinemethanol (CAS Registry No.208519-37-3) (21.5 g, 75 mmol) was dissolved in hexamethylphosphoramide(210 mL). Over a period of 30 min sodium hydride (3.0 g of 60%dispersion in oil, ˜75 mmol) was added with stirring at roomtemperature. The mixture was stirred for another 45 min at roomtemperature and 2,2,2-trifluoroethyl trifluoromethane sulfonate (12.5mL, 90 mmol) was added drop wise with stirring and temperature control(<40° C.). The mixture was stirred for 18 h at 120° C., cooled to roomtemperature and poured into water (800 mL). The mixture was acidifiedwith 2N—HCl (50 mL) and extracted with ethyl acetate (2×350 mL). Organicphases were washed with water (2×400 mL), pooled and dried with Na₂SO₄.Solvents were evaporated and the brown, solid residue (27.9 g) waspurified by chromatography on silica with ethyl acetate/n-heptane (1:1)to give the title compound as a white solid (24.8 g, 90%), LC-MS (UVpeak area/ESI) 100%, 367.916 (M+H)⁺.

Example B Preparation of6-chloro-4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol

[4-Iodo-6-chloro-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol (24.7g, 67 mmol) was suspended in toluene (300 mL). Under Argon was added[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)dichloridedichloromethane adduct (1.65 g, 2 mmol), 4-chlorophenyl-boronic acid(10.5 g, 67 mmol) and 2.0 M Na₂CO₃-solution (67.2 mL, 134 mmol) withstirring. The mixture was stirred for 90 min at 90° C. and cooled toroom temperature. Water (150 mL) was added and the mixture was extractedwith ethyl acetate (2×150 mL); organic phase were pooled and dried withNa₂SO₄. Solvents were evaporated and the brown, oily residue (27.7 g)was purified by chromatography on silica with ethyl acetate/n-heptane(1:2) to give the title compound as a brown oil (24.1 g, quant), LC-MS(UV peak area/ESI) ˜100%, 352.0116 (M+H)⁺.

Example C Preparation of[4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol

6-Chloro-4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol(24.1 g, 68 mmol) was dissolved in acetic acid (80 mL). The solution waswarmed to 40° C., tetramethylammoniumbromide (0.105 g, 0.7 mmol) wasadded and activated zinc-powder (26.8 g, 410 mmol) was added in portions(2 g every 30 min) with stirring (argon atmosphere). The suspension wasstirred for 16 h at 50° C. after which time another batch of activatedzinc-powder (10 g, in 5 portions of 2 g each) was added. Stirring at 50°C. continued for another 3 h after which time the mixture was cooled toroom temperature and poured into water (1000 mL).

Concentrated NaOH solution (˜150 mL) was added till pH 14 was attained.Ethyl acetate (500 mL) was added and the mixture stirred in the cold for15 min. The suspension was filtered through Celite® was and the filtercake thoroughly washed with ethyl acetate (5×300 mL). The filtrate wascollected, phases were separated, the water phase was extracted oncewith ethyl acetate (500 mL), and organic phases were pooled and driedwith Na₂SO₄. Solvents were evaporated and the brown, solid residue (21.1g) was purified by chromatography on silica with ethyl acetate/n-heptane(2:1) to give the title compound as a off white solid (17.4 g, 80%),LC-MS (UV peak area/ESI) 100%, 318.050 (M+H)⁺.

Example D Preparation of4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid

[4-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol(17.4 g, 55 mmol) was dissolved in acetonitrile (235 mL). Phosphatebuffer (pH 6.7, 220 mL) and 2,2,6,6-tetra-methylpiperidine 1-oxylradical (TEMPO, 0.6 g) was added and the solution was warmed to 35° C.To this warm solution under argon was added with stirring over 2 hsimultaneously a solution of NaOCl₂ (12.4 g) in water (58 mL) and NaOCl(0.85 mL, 10% solution) in water (35 mL). Stirring was continued for 20h at 35° C. after which time the solution was cooled to room temperatureand quenched by addition of in sequence water (420 mL), 2 N NaOHsolution (65 mL) and Na₂SO₃ solution (17.1 g in 285 mL water). Thismixture was stirred for 30 min and acidified with 2 N HCl (175 mL). Themixture was extracted once with ethyl acetate/THF (800/150 mL), and oncewith ethyl acetate (500 mL). Organic phases were washed with brine (800mL), pooled and dried with Na₂SO₄. The solvent phase was concentrated toa volume of ˜100 mL, n-heptane (150 mL) was added and the solvent phasewas concentrated again to ˜100 mL. This was repeated twice. n-Heptane(100 mL) was added. The product precipitated upon stirring, was filteredoff and dried to give the title compound as a white solid (18.4 g,quant.), LC-MS (UV peak area/ESI) ˜100%, 332.029 (M+H)⁺.

Example E Preparation of(6-chloro-4-iodo-5-cyclopropylmethoxy-pyridin-2-yl)-methanol

The title compound was synthesized in analogy to Example A, using6-chloro-5-hydroxy-4-iodo-2-pyridinemethanol and cyclopropylmethylbromide as starting materials; LC-MS (UV peak area/ESI) 95.8%, 339.9584(M+H)⁺.

Example F Preparation of[6-Chloro-4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridin-2-yl]-methanol

The title compound was synthesized in analogy to Example B, using6-chloro-4-iodo-5-cyclopropylmethoxy-pyridin-2-yl)-methanol and4-chlorophenyl-boronic acid as starting materials; LC-MS (UV peakarea/ESI) 100%, 324.0551 (M+H)⁺.

Example G Preparation of[4-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridin-2-yl]-methanol

The title compound was synthesized in analogy to Example C, using[6-chloro-4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridin-2-yl]-methanolas starting material; LC-MS (UV peak area/ESI) 91.4%, 290.0933 (M+H)⁺.

Example H Preparation of4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid

The title compound was synthesized in analogy to Example D, using[4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridin-2-yl]-methanol asstarting material; LC-MS (UV peak area/ESI)-%, 304.0742 (M+H)⁺.

Example I Preparation of6-chloro-3-(2,2,2-trifluoro-ethoxy)-pyridazin-4-ylamine

To a solution of 3.28 g 3,6-dichloro-pyridazin-4-ylamine in 30 mLdimethylsulfoxide and 4.0 g trifluoroethanol was added 1.84 g lithiumhydroxide hydrate and 3 mL water and the mixture was heated to 80° C.for 18 h. The reaction mixture was diluted with 100 mL water and stirredat ambient temperature for 2 h. The resulting solid was collected byfiltration washed with water and dried to constant weight under highvacuum to yield 3.84 g of the title compound as off white crystals, MS228.1 and 230.1 (M+H)⁺.

Example J Preparation of4-bromo-6-chloro-3-(2,2,2-trifluoro-ethoxy)-pyridazine

To a suspension of 2.30 g6-chloro-3-(2,2,2-trifluoro-ethoxy)-pyridazin-4-ylamine in 23 mLdibromomethane was added 5.11 g isoamylnitrite at once and drop wise4.642 g trimethylbromosilane at ambient temperature (during ca 10 min).A moderate exotherm was observed and a dark brown solution was obtained.The mixture was stirred at ambient temperature for 18 h. The solventswere evaporated and the residue was purified (3×) by chromatography onsilica gel using a gradient of heptane to dichloromethane to yield 0.70g of the title compound as white crystalline solid, MS 292 (M+H)⁺.

Example K Preparation of6-chloro-4-(4-chloro-phenyl)-3-(2,2,2-trifluoro-ethoxy)-pyridazine

A mixture of 0.676 g4-bromo-6-chloro-3-(2,2,2-trifluoro-ethoxy)-pyridazine, 363 mg4-chlorophenylboronic acid, 641 mg potassium carbonate and 134 mgtetrakis(triphenylphosphine) palladium in 15 mL tetrahydrofuran and 15mL water was heated to reflux for 18 h. The reaction mixture waspartitioned between water and ethyl acetate. The phases were separatedand the organic phase was purified by chromatography on silica gel usinga gradient of heptane: ethyl acetate of 95:5 to 50:50 to yield 0.493 gof the title compound as white solid, MS 323.1 (M+H)⁺.

Example L Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid methyl ester

To a solution of 0.882 g6-chloro-4-(4-chloro-phenyl)-3-(2,2,2-trifluoro-ethoxy)-pyridazine inmethanol was added 0.626 g triethylamine and 0.081 g PdCl₂.dppf. CH₂Cl₂.The mixture was heated to 110° C. under an atmosphere of 70 bar carbonmonoxide for 20 h. The reaction mixture was cooled to room temperature.The solids were removed by filtration and the mother liquor wasevaporated and purified by chromatography on silica gel using a gradientof heptane:ethyl acetate of 95:5 to 50:50 to yield 0.870 g of the titlecompound as white solid, MS 347.1 (M+H)⁺.

Example M Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid

To a solution of 0.865 g5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid methyl ester in 9.0 mL tetrahydrofuran was added 3.2 mL of a 1M oflithium hydroxide in water was added and the mixture was stirred atambient temperature for 3 h. The reaction mixture was acidified with 1Mhydrochloric acid. The solid was collected by filtration washed withwater and dried under high vacuum to yield 0.805 g of the title compoundas white solid, 331.1 (M−H)⁻.

Example N Preparation of 3-chloro-6-cyclopropylmethoxy-pyridazine

To a solution of 1.016 mL cyclopropanemethanol in 10 mLdimethylsulfoxide was added 0.564 g sodium hydride 55% in mineral oiland the mixture was stirred at room temperature for 15 min. Theresulting solution was added drop wise to a solution of 2.0 g3,6-dichloropyridazine in 20 mL dry dimethylsulfoxide at roomtemperature and stirred at this temperature for 1 h. The reactionmixture was partitioned between water and ethyl acetate, the phases wereseparated and the organic phase was purified by chromatography on silicagel using a gradient of heptane:ethyl acetate=95:5 to 40:60 to yield1.88 g of the title compound as white solid, MS 185.05 (M+H)⁺.

Example O Preparation of6-chloro-3-cyclopropylmethoxy-4-iodo-pyridazine)

To a solution of 0.988 mL 2,2,6,6-tetramethylpiperidine in 10 mLtetrahydrofuran was added 3.534 mL of a 1.6M solution of n-butyl lithiumin hexane at ambient temperature and the mixture was stirred at roomtemperature for 30 min. To this solution was added rapidly a precooled(−75° C.) solution of 0.300 g 3-chloro-6-cyclopropylmethoxy-pyridazinein 10 mL tetrahydrofuran at −75° C. After 5 minutes, a precooledsolution of 0.701 g iodine in 10 mL THF was added rapidly. The reactionmixture was stirred at −75° C. for 30 minutes and then quenched with asaturated aqueous solution of ammonium chloride and diluted with ethylacetate. The phases were separated and the organic phase was purified bychromatography on silica gel using a gradient of heptane:ethylacetate=95:5 to 50:50 to yield 0.206 g of the title compound as lightyellow solid, MS 310.9 (M+H)⁺.

Example P Preparation of5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridazine-3-carboxylic acid

The title compound was synthesized in analogy to examples J to M bysubstituting 4-bromo-6-chloro-3-(2,2,2-trifluoro-ethoxy)-pyridazine with6-chloro-3-cyclopropylmethoxy-4-iodo-pyridazine the title compound wasobtained as white solid, MS 303.1 (M−H)⁻.

Example Q Preparation of2-chloro-4-(4-chloro-phenyl)-5-fluoro-pyrimidine

A mixture of 5.0 g 2,4-dichloro-5-fluoropyrimidine, 4.683 gp-chlorophenylboronic acid, 1.730 g tetrakistriphenylphosphinpalladiumand 8.278 g potassium carbonate in 125 mL tetrahydrofuran and 125 mLwater was heated to reflux for 3 h. The reaction mixture was cooled toroom temperature and diluted with ethyl acetate. The phases wereseparated and the organic phase was washed with brine dried over sodiumsulfate and evaporated. The solid residue was triturated in ca 60 mLmethanol for 30 min. The solids were collected by filtration to yield5.2 g of an off white solid (contains some boronic acid which gives astart spot). The mother liquor was evaporated and the residue waspurified by chromatography on silica gel with heptane:ethyl acetate=8:2to 1:1 to yield 1.0 g of the product as white solid. Both crops werecombined and dissolved in ca 50 mL dichloromethane and filtered over ca50 g silica gel with dichloromethane to remove a polar start spot. Thefiltrate was concentrated under aspirator vacuum whereby precipitationoccurred. The solid was collected by filtration to yield 5.76 g of thetitle compound as white crystals, MS 230.1 and 228.1 (M+H)⁺.

Example R Preparation of2-chloro-4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine

To a solution of 0.948 mL cyclopropanemethanol in 13 mLdimethylformamide was added 0.468 g sodium hydride 55% in mineral oiland the reaction mixture was stirred at room temperature for 15 min. Theresulting solution was added drop wise to a solution of 2.586 g2-chloro-4-(4-chloro-phenyl)-5-fluoro-pyrimidine at 0° C. and themixture was stirred at 0° C. for 30 min. The reaction mixture waspartitioned between water and ethyl acetate. The phases were separatedand the organic phase was purified by chromatography on silica gel usinga gradient of heptane:ethyl acetate=10:90 to 80:20 to yield 2.50 g ofthe title compound as white solid, MS 295.2 (M+H)⁺.

Example S Preparation of4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acidmethyl ester

The title compound was synthesized in analogy to example L bysubstituting6-chloro-4-(4-chloro-phenyl)-3-(2,2,2-trifluoro-ethoxy)-pyridazine with2-chloro-4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine the titlecompound was obtained as white solid, MS 319.2 (M+H)⁺.

Example T Preparation of4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid

To a solution of 2.655 g4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acidmethyl ester in 27 mL tetrahydrofuran was added 11 mL of a 1M solutionof lithium hydroxide in water and the mixture was stirred at roomtemperature for 1 h. The reaction mixture was acidified by addition of1M hydrochloric acid. The precipitate was collected by filtration washedwith water and dried to constant weight under high vacuum to yield 2.473g of the title compound as white solid, MS 305.1 (M+H)⁺.

Example U Preparation of4-(4-Chloro-phenyl)-5-fluoro-pyrimidine-2-carboxylic acid methyl ester

To a solution of 0.200 g2-chloro-4-(4-chloro-phenyl)-5-fluoro-pyrimidine was in 2 ml methanolwas added 0.020 g PdCl₂.dppf.CH₂Cl₂ and 0.176 g triethylamine and themixture was stirred under an atmosphere of 70 bar carbon monoxide at130° C. for 20 hours. The solids were removed by filtration and themother liquor was purified by chromatography on silica gel with agradient of heptane:ethyl acetate=8:2 to ethyl acetate to yield 0.032 g(14.58%) of the title compound as off-white solid, MS 267.1 (M+H)⁺.

Example V Preparation of4-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid methyl ester

To a solution of 0.143 g4-(4-chloro-phenyl)-5-fluoro-pyrimidine-2-carboxylic acid methyl esterin 1.5 ml dried DMSO was added 192 mg of cesium carbonate and 0.059 g of2,2,2-trifluoroethanol and the mixture was stirred at 60° C. for 2hours. The reaction mixture was partitioned between water and ethylacetate, the phases were separated and the organic phase was dried withMgSO₄ and purified by chromatography on silica gel with a gradient ofheptane:ethyl acetate=9:1 to 1:1 to yield 161 mg (86.60%) of the titlecompound as white solid, MS 347.1 (M+H)⁺.

Example W Preparation of4-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid

To a solution of4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid methyl ester in 2.5 ml THF was added 937 μL of a 1M LiOH solutionin water and the reaction mixture was stirred at room temperature for 30minutes. The reaction mixture was acidified with 1M hydrochloric acidsolution and the formed precipitate was collected by filtration washedwith water and dried under high vacuum to yield 232 mg (96.71%) of thetitle compound as white solid, MS 331.1 (M+H)⁺.

Example X Preparation of2-Chloro-4-(3,4-dichloro-phenyl)-5-fluoro-pyrimidine

A mixture of 20 g 2,4-dichloro-5-fluoropyrimidine, 22.86 g3,4-dichlorophenylboronic acid, 33.11 g potassium carbonate and 6.92 gtetrakis(triphenylphosphine)palladium were in 500 mL THF and 500 mLwater was heated to reflux for 4 h. The reaction mixture was cooled toroom temperature diluted with water and ethyl acetate. The phases wereseparated and the organic phase was purified by chromatography on silicagel with dichloromethane to yield 24.640 g (74.13%) of the titlecompound as white solid, MS 279.1 (M+H)⁺.

Example Y Preparation of2-Chloro-4-(3,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine

To a mixture of 2.0 ml 2,2,2-trifluoroethanol in 35 mL dry DMF was added1.1 g sodium hydride was added and the mixture was stirred at roomtemperature for 15 minutes. The resulting solution was added drop wiseat −10° C. to a solution of 7 g2-chloro-4-(3,4-dichloro-phenyl)-5-fluoro-pyrimidine in 50 mL dry DMFduring 39 min. The reaction mixture was then stirred at room temperaturefor 2 h. The resulting brown mixture was partitioned between water andethyl acetate, the phases were separated the organic phase was driedover MgSO₄ and purified by chromatography on silica gel with a gradientof heptane:dichloromethane=1:1 to dichloromethane to yield 5.575 g(61.81%) of the title compound as light yellow solid, MS 356.9 (M+H)⁺.

Example Z Preparation of4-(3,4-Dichloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid methyl ester

To a solution of 5.470 g2-chloro-4-(3,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidinewas dissolved in 100 mL methanol was added 1.093 g PdCl₂.dppf.CH₂Cl₂ and3.096 g triethylamine and the mixture was stirred under an atmosphere of70 bar carbon monoxide at 110° C. for 20 hours. The solids were removedby filtration and the mother liquor was purified by chromatography onsilica gel with a gradient of heptane:ethyl acetate=9:1 to 1:1 to yield4.49 g (60.45%) of the title compound as white solid, MS 382.2 (M+H)⁺.

Example AA Preparation of4-(3,4-Dichloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid

To a solution of 3.79 g4-(3,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid methyl ester in 28 mL tetrahydrofuran was added 13 mL of a 1Msolution of lithium hydroxide in water and the mixture was stirred atroom temperature for 1 h. The reaction mixture was acidified by additionof 1M hydrochloric acid. The precipitate was collected by filtrationwashed with water and dried to constant weight under high vacuum toyield 3.561 g (97.55%) of the title compound as white solid, MS 365.0(M−H)⁻.

Example AB Preparation of6-Chloro-2-(4-chloro-phenyl)-3-(2,2,2-trifluoro-ethoxy)-pyridine

A solution of 2.2 g 2,4-chloro-5-fluoropyridine, 2.28 g4-chlorophenylboronic acid and 0.6 g tetrakistriphenylphosphinpalladiumin 30 mL tetrahydrofuran was added 30 mL of a 10% a solution ofpotassium carbonate in water and the mixture was stirred at ambienttemperature for 18 h. The reaction mixture was diluted with ethylacetate and water. The phases were separated and the organic phase waswashed water, 10% aqueous citric acid, 10% aqueous sodium bicarbonateand brine, dried over sodium sulfate and evaporated. The residue waspurified by chromatography on silica gel with a gradient ofheptane:dichloromethane=9:1 to 1:1 (only starting spot was removed) Theproduct fractions were collected and evaporated. The residue wassubjected to kugelrohr distillation at 0.03 mBar and 110° C. to yield1.72 g of the title compound as colorless oil which solidified intowhite crystals, MS 241 and 243 (M+H)⁺.

Example AC Preparation of6-Chloro-2-(4-chloro-phenyl)-3-(2,2,2-trifluoro-ethoxy)-pyridine

To a solution of 1.273 g trifluoroethanol in 20 mL dimethylsulfoxide wasadded 0.463 g sodiumhydride 55% in oil and the mixture was stirred atroom temperature for 15 min. To the resulting solution was added asolution of 3.2 g6-chloro-2-(4-chloro-phenyl)-3-(2,2,2-trifluoro-ethoxy)-pyridine in 10mL dimethylsulfoxide and the mixture was stirred at room temperature for3 h. The reaction mixture was partitioned between water and ethylacetate. The phases were separated and the organic phase was purified bychromatography on silica gel with a gradient of heptane todichloromethane to yield 3.30 g of the title compound as slightly yellowsolid, at 322.1 and 324.2 (M+H)⁺. The product was obtained as 85:15mixture of F vs Cl substitution products that were better separable atthe next step.

Example AD Preparation of6-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid methyl ester

To a solution of 3.30 g6-chloro-2-(4-chloro-phenyl)-3-(2,2,2-trifluoro-ethoxy)-pyridine was in100 mL methanol was added 0.8 g PdCl₂.dppf.CH₂Cl₂ and 2.5 gtriethylamine and the mixture was stirred under an atmosphere of 70 barcarbon monoxide at 110° C. for 20 hours. The solids were removed byfiltration and the mother liquor was purified by chromatography onsilica gel with a gradient of heptane:ethyl acetate=9:1 to 1:1 to yieldca 3 g of the title compound as white solid, MS 346.2 (M+H)⁺.

Example AE Preparation of6-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid

To a solution of 3.0 g6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid methyl ester in 30 mL tetrahydrofuran was added 14 mL of a 1Msolution of lithium hydroxide in water and the mixture was stirred atroom temperature for 1 h. The reaction mixture was acidified by additionof 1M hydrochloric acid. The precipitate was collected by filtrationwashed with water and dried to constant weight under high vacuum toyield 2.36 g of the title compound as white solid, MS 330.3 (M−H)⁻.

Example AF Preparation of5-(4-Chloro-phenyl)-6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridazine-3-carboxylicacid

The compound was prepared in analogy to Examples Ito M by substitutingtrifluoroethanol with (S)-1,1,1-trifluoro-propan-2-ol in theetherification step. The title compound was obtained as off-white foam,MS 345.1 (M−H)⁻.

Example AG Preparation of (S)-methyl6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylate

To a solution of methyl 5-bromo-6-(4-chlorophenyl)pyrazine-2-carboxylate(0.847 g, 2.59 mmol, Eq: 1.00) in dry DMSO (8 ml) was added cesiumcarbonate (1.54 g, 2.84 mmol, Eq: 1.1) and(S)-1,1,1-trifluoro-2-propanol (324 mg, 233 μl, 2.84 mmol, Eq: 1.1) andthe reaction mixture was stirred at room temperature for 3 hours. Thereaction mixture was partitioned between water and ethyl acetate, thephases were separated and the organic phase was dried over MgSO₄evaporated and purified by flash chromatography (silica gel, 100 g, 10%to 50% EtOAc in heptane) to yield the title compound as light yellow oil(0.724 g, 77.6%), MS 361.1 (M+H)⁺.

Example AH(S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylicacid

To a suspension of (S)-methyl6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylate(0.72 g, 2.00 mmol, Eq: 1.00) in tetrahydrofuran (7 mL) was added a 1MLiOH solution in water (2.59 ml, 2.59 mmol, Eq: 1.3) and the reactionmixture was stirred at room temperature for 1 hour. The mixture wasconcentrated to remove tetrahydrofuran and diluted with water; acidifiedwith 1M hydrochloric acid to pH 2 and extracted with ethyl acetate. Theorganic phase was dried with MgSO₄; filtered, evaporated and dried toconstant weight under high vacuum to yield the title compound as whitesolid (0.70 g, 100%), MS 345.0 (M−H)⁻.

Example AI Preparation ofC-(5-Trifluoromethyl-[1,2,4]oxadiazol-3-yl)-methylamine hydrochloride

To a solution of 1.89 g (N-hydroxycarbamimidoylmethyl)-carbamic acidtert-butyl ester in 20 mL acetonitrile was added 7.746 g Huenig's baseand 6.294 g trifluoroacetic acid anhydride (exotherm) and the mixturewas stirred at room temperature for 2 h. The reaction mixture waspartitioned between 10% citric acid and ethyl acetate. The phases wereseparated and the organic phase was washed with 10% sodium bicarbonateand brine dried over magnesium sulfate and evaporated. The residue wasdried under high vacuum and purified by chromatography on silica gelwith a gradient of heptane:ethyl acetate=9:1 to 1:1. The productfraction were combined and concentrated whereby crystallizationoccurred. The solid was collected by filtration and dried to constantweight to yield 1.00 g white crystals. These were dissolved up in 3 mLof a 4M solution of hydrochloric acid in dioxane and the mixture wasstirred at ambient temperature for 18 h. The formed solid was collectedby filtration washed with ethyl acetate and dried to constant weight toyield 0.43 g of the title compound as white crystals, MS 166.0 (M−H)⁻.

Example AJ Preparation of(3-Trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-carbamic acid tert-butylester

To a solution of 0.821 g Boc-glycine in 8 ml dichloromethane was added0.967 g dicyclohexylcarbodiimide and the mixture was stirred at roomtemperature for 30 min. To the resulting white suspension was added asolution of 0.60 g 2,2,2-trifluoro-N-hydroxy-acetamidine in 6 mldichloromethane (an almost clear solution is obtained initially and awhite precipitate forms after ca 5 min) and the mixture was stirred atroom temperature for 2 h. The solid was removed by filtration and themother liquor was purified by chromatography on silica gel with agradient of heptane:ethyl acetate=8:2 to ethyl acetate to yield 0.66 gwhite crystals. A mixture of 0.57 g of these crystals in 10 ml toluenewas heated under a dean stark trap to reflux for 5 h. The solvent wasevaporated and the residue was purified by chromatography on silica gelwith a gradient of heptane:ethyl acetate=9:1 to 1:1 to yield 0.29 g ofthe title compound as colorless oil, MS 266.2 (M−H)⁻.

Example AK Preparation of3-Trifluoromethyl-[1,2,4]oxadiazol-5-methanamine hydrochloride

To a solution of 0.29 g(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-carbamic acid tert-butylester in 3 ml ethyl acetate was added 1.5 ml of a 4M solution ofhydrochloric acid in dioxane and the mixture was stirred at ambienttemperature for 18 h. The resulting clear solution was evaporated andthe residue was triturated under ethyl acetate. The solid was collectedby filtration and dried to constant weight under high vacuum to yield0.145 g of the title compound as white crystals, 169.2 (M+H)⁺.

Example AL Preparation of 5-Chloro-3-(4-chloro-phenyl)-2-fluoro-pyridine

In analogy to Example K by substituting4-bromo-6-chloro-3-(2,2,2-trifluoro-ethoxy)-pyridazine with3-bromo-5-chloro-2-fluoropyridine in the Suzuki step the title compoundwas obtained as white solid, 241 (M+H)⁺.

Example AM Preparation of5-Chloro-3-(4-chloro-phenyl)-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine

To a mixture of 1.133 g (S)-1,1,1-trifluor-2-propanol in 10 ml dry DMF397 mg sodium hydride (60%) was added and the mixture was stirred atroom temperature for 30 minutes. The resulting solution was addeddropwise at RT to a solution of 2.185 g5-chloro-3-(4-chloro-phenyl)-2-fluoro-pyridine in 20 ml dry DMF. Thereaction mixture was then stirred at room temperature for 2 h. Theresulting light yellow mixture was partitioned between water and ethylacetate, the phases were separated. The organic phase was dried overMgSO4 and purified by chromatography on silica gel with a gradient ofheptane to heptane:ethyl acetate=9:1 to yield 2.330 g (76.80%) of thetitle compound as colorless liquid, 336.1 (M+H)⁺.

Example AN Preparation of (S)-methyl5-(4-chlorophenyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinate

To a solution of 2.42 g5-chloro-3-(4-chloro-phenyl)-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridinein 50 mL methanol was added 1.09 g triethylamine and 0.484 gPdCl₂.dppf.CH₂Cl₂. The mixture was heated to 150° C. under an atmosphereof 70 bar carbon monoxide for 20 h. The reaction mixture was cooled toroom temperature. The solids were removed by filtration and the motherliquor was evaporated and purified by chromatography on silica gel usinga gradient of heptane to heptane:ethyl acetate 85:15 to yield 0.862 g(33%) of the title compound as a light yellow oil, 359 (M).

Example AO Preparation of(S)-5-(4-Chlorophenyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinic acid

To a solution of 0.860 g (S)-methyl5-(4-chlorophenyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinate in 9 mLtetrahydrofuran was added 3 mL of a 1M solution of lithium hydroxide inwater and the mixture was stirred at room temperature overnight. Thesolvent was evaporated and the residue was acidified by addition of 1Mhydrochloric acid till pH=2. Ethyl acetate was added and the phases wereseparated. The organic phase was dried over MgSO₄ and the solvent wasremoved to yield 830 mg (100%) of the title compound as light yellowsolid, MS 344.1 (M−H)⁻.

Example AP Preparation of (S)-Methyl4-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxylate

The compound was prepared in analogy to examples R and S by substitutingcyclopropanemethanol with (S)-1,1,1-trifluor-2-propanol and2-chloro-4-(4-chloro-phenyl)-5-fluoro-pyrimidine with2-chloro-4-(4-chloro-phenyl)-5-fluoro-pyrimidine. The title compound wasobtained as white solid, MS 361.2 (M+H)⁺.

Example AQ Preparation of(S)-4-(4-Chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxylicacid

The title compound was obtained in analogy to Example AO by substituting(S)-methyl5-(4-chlorophenyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinate with(S)-methyl4-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxylateas white solid, MS 345.0 (M−H)⁻.

Example AR Preparation of(S)-4-(4-Chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)picolinic acid

The title compound was obtained in analogy to Examples AL to AO bysubstituting 3-bromo-5-chloro-2-fluoropyridine with2-chloro-5-fluoro-4-iodopyridine in the Suzuki coupling as a whitesolid, MS 344.1 (M−H)⁻.

Example AS Preparation of 2-(4-Chloro-phenyl)-3-fluoro-pyridine

A solution of 18.60 g 2-chloro-3-fluoropyridine, 23.25 g4-chlorophenylboronic acid and 2.30 g1,1′bis(diphenylphosphino)ferrocenedichloropalladium(II), 22.50 g sodiumcarbonate in toluol:dimethylformamide:water 190:20:40 and the mixturewas stirred at 90° C. over 5 hours. The reaction mixture was dilutedwith ethyl acetate and water. The phases were separated and the organicphase was washed with brine, dried over magnesium sulfate andevaporated. The residue was purified by chromatography on silica gelwith a gradient of heptane to heptane:ethyl acetate 1:1. The productfractions were collected and evaporated. The residue was crystallized inether to yield 19.30 g (65.73%) of the title compound as off-whitesolid, MS 208.1 (M+H)⁺.

Example AT Preparation of2-(4-Chloro-phenyl)-3-cyclopropylmethoxy-pyridine

To a mixture of 16.20 g cyclopropanmethanol in 150 ml dry DMSO 11 gsodium hydride (55%) was added and the mixture was stirred at roomtemperature for 30 minutes. A solution containing 37.30 g2-(4-chloro-phenyl)-3-fluoro-pyridine in 50 mL dry DMSO was addeddropwise. The reaction mixture was then stirred at room temperature for3 h. The resulting suspension was partitioned between water andmethylene chloride, the phases were separated. The organic phase waswashed with brine; then dried over MgSO₄ and purified by chromatographyon silica gel with a gradient of heptane to heptane:ethylacetate=2:1 toyield 34.95 g (74.90%) of the title compound as yellow oil, MS 260.1(M+H)⁺.

Example AU Preparation of2-(4-Chloro-phenyl)-3-cyclopropylmethoxy-pyridine 1-oxide

To a solution of 5 g 2-(4-chloro-phenyl)-3-cyclopropylmethoxy-pyridinein 15 mL acetic acid, 3 mL hydrogenperoxyde (30% in water) was added.The reaction mixture was then stirred at 70° C. for 15 h. The reactionmixture was diluted with water and quenched with sodium carbonate. Themixture was washed with methylene chloride. The organic phase was washedwith water; then dried over MgSO₄ and purified by chromatography onsilica gel with a gradient of ethyl acetate to ethyl acetate:methanol4:1 to yield 3.46 g (65.19%) of the title compound as white solid, MS276.1 (M+H)⁺.

Example AV Preparation of6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carbonitrile

To a solution of 25 g 2-(4-chloro-phenyl)-3-cyclopropylmethoxy-pyridine1-oxide in 500 mL acetonitrile, 9.23 g triethylamine and 10.73 gdimethylcarbamoylchlorid were added. After 5 minutes at roomtemperature, 27.88 g trimethylsilylcyanid was added. The reactionmixture was stirred at 90° C. over 15 h. The reaction mixture waspartitioned between water and ethyl acetate; then extracted. The organicphase was washed with brine; then dried over MgSO₄ and purified bychromatography on silica gel with a gradient of heptane to heptane:ethylacetate 2:1 to yield 15.30 g (59.26%) of the title compound as lightyellow solid, MS 285.1 (M+H)⁺.

Example AW Preparation of6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid

8.27 g acetylchloride was added dropwise to 120 mL ethanol at 0° C.After 5 minutes, 6 g6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carbonitrile wasadded at 0° C. The reaction mixture was stirred at 90° C. over 20 h. Thereaction mixture was partitioned between water and ethyl acetate; thenextracted. The organic phase was washed with brine; then dried overMgSO₄. The crude product was stirred at room temperature intetrahydrofuran:water 45:20. 1.77 g lithium hydroxide was added. Thereaction mixture was stirred at 80° C. over 7 hours. The reactionmixture was added over acetic acid and extracted with dichloromethane.The organic phase was washed with water; then dried over MgSO₄ andpurified by chromatography on silica gel with a gradient of heptane toheptane:ethyl acetate 2:1 to yield 4.50 g (70.31%) of the title compoundas light yellow solid, MS 304.1 (M+H)⁺.

Example AX Preparation of5-(tert-Butyldimethylsilyloxy)-1,1,1-trifluoropent-3-yn-2-one

To 50 mL of a 1.6M solution of n-BuLi (0.080 mol, 1 equ) in hexanes wasadded dropwise tert-butyldimethyl(prop-2-ynyloxy)silane (13.57 g; 0.080mol; 1 equ) with dry ice acetone cooling. After addition the dry iceacetone bath was replaced by an ice acetone bath. When the mixturebecame difficult to stir toluene (25 mL) was added. The mixture becameclear and was stirred at −10° C. for 15 min. To the resulting slightlyyellow solution was added ethyl 2,2,2-trifluoroacetate (11.3 g; 0.080mol; 1 equ) with cooling in a dry ice acetone bath (ca <−40° C.). Afteraddition the dry ice acetone bath was replaced by an ice acetone bathand the mixture was stirred with thawing to room temperature for 18 h.The reaction mixture was poured onto ice mixed with 10% aqueous citricacid. The phases were separated and the organic phase was washed with10% aqueous sodium bicarbonate and brine and purified by filtration overca 350 g silica gel using heptane:dichloromethane=1:1 as eluent. Theproduct fractions (dichloromethane:heptane 1:1; r.f.:0.3 KMnO4 staining)were pooled and evaporated to yield the title compound as an orangeyellow oil (16.0 g, 75.4% Th), MS 266.277 (M.)⁺.

Example AY Preparation of (3-(Trifluoromethyl)isoxazol-5-yl)methanol

To a solution of hydroxylamine hydrochloride (0.694 g 0.010 mol, 1 equ)and 0.02 g sodium hydroxide in 25 mL methanol was added5-(tert-butyldimethylsilyloxy)-1,1,1-trifluoropent-3-yn-2-one (2.66 g0.010 mol, 1 equ) and the mixture was heated to reflux for 3 h. Thereaction mixture was extracted with ethyl acetate and purified bychromatography on silica gel (50 g) using a gradient of heptane:ethylacetate=9:1 to 1:1. to yield 0.524 g of the title compound as colorlessoil, MS 167 (M.)⁺.

Example AZ Preparation of 5-(Bromomethyl)-3-(trifluoromethyl)isoxazole

To a solution of (3-(trifluoromethyl)isoxazol-5-yl)methanol (2.5 g, 15mmol) in dimethylformamide (25 mL) was added drop wise tribromophosphine(4.64 g 17.1 mmol, 1.15 eq) and the mixture was stirred at 0° C. for 15min and at ambient temperature for 2 h. The reaction mixture waspartitioned between 10% sodium bicarbonate and dichloromethane. Thephases were separated and the organic phase was washed with water andpassed over a plug of silica eluting with dichloromethane. The UV activeproduct fractions were collected and evaporated to yield the titlecompound as colorless oil (2.04 g 59.3%), MS 229 and 231 (M.)⁺.

Example BA Preparation of (3-(Trifluoromethyl)isoxazol-5-yl)methanaminehydrochloride

To a solution of di-tert-butyl iminodicarbonate in dimethylsulfoxide wasadded sodium hydride 55% in oil (0.30 g, 7.5 mmol, 1.1 eq) and themixture was stirred for 30 min at ambient temperature. To the resultingwhite suspension was added dropwise5-(bromomethyl)-3-(trifluoromethyl)isoxazole (1.5 g, 6.52 mmol, 1 eq). Amoderate exothermic reaction was observed. The resulting dark lilacsuspension was stirred at ambient for 2 h. The reaction mixture waspartitioned between water and heptane (the reaction mixture brightenedto a pale yellow). The phases were separated and the organic phase waspurified by chromatography on silica gel with heptane:ethyl acetate=9:1to yield a colorless oil (1.90 g) which was taken up in 4M hydrochloricacid in dioxane (10 mL) and stirred at ambient temperature for 18 h. Theresulting precipitate was collected by filtration washed with dioxaneand dried to constant weight under high vacuum to yield the titlecompound as white crystals (0.96 g 72.6% Th), MS 165 (M.)⁺.

Example BB Preparation of 5-Trifluoromethyl-isoxazole-3-carboxylic acidethyl ester

To a solution of 11.44 g ethyl 5,5,5-trifluoro-2,4-dioxopentanoate butylester in 75 ml ethanol was added 11.2 g hydroxylamine hydrochloride andthe mixture was stirred at reflux for 2 h. The reaction mixture wasevaporated and extracted with 100 mL ethyl acetate and 50 mL water. Theaqueous layer was back-extracted with 100 mL ethyl acetate. The organiclayers were washed with water (2×50 mL). The combined org. layer wasdried over Na2SO4, filtered off and concentrated in vacuo. The residuewas dissolved in 75 mL toluene. 200 μL pyridine and 7.9 mlthionylchloride were added and the mixture was stirred at reflux for 30min. The reaction mixture was concentrated in vacuo and extracted with50 ml ice water and 100 ml ethyl acetate. The aqueous layer wasback-extracted with 100 ml ethyl acetate. The organic layers were washedwith ice water (2×50 ml). The combined org. layer was dried over Na2SO4,filtered off and concentrated in vacuo. The crude material was purifiedby flash chromatography over a 500 g SiO2-column with ethylacetate/heptane 1:1 as eluent to yield 7.5 g of the title compound as abrown oil. MS (ESI): 208 (M−H)⁺

Example BC Preparation of (5-Trifluoromethyl-isoxazol-3-yl)-methanol

To a solution of 7.5 g 5-trifluoromethyl-isoxazole-3-carboxylic acidethyl ester in 85 mL ethanol was added 3.66 g sodium hydride portionwise at RT. The reaction mixture was stirred at RT for 16 h. 100 mL 1MHCl were added drop by drop under ice-bath cooling. The reaction mixturewas extracted with 250 mL diethyl ether and 200 mL sat. NaClsolution/water mixture 1:1. The aqueous layer was back-extracted withdiethyl ether (2×100 mL). The org. layers were washed with sat. NaClsolution/water mixture 1:1 (2×200 mL). The combined org. layer was driedover Na₂SO₄, filtered off and concentrated in vacuo to yield 5.8 g ofthe title compound as brown oil. MS (EI): 167 (M+H)⁺.

Example BD Preparation of 5-(Trifluoromethyl)isoxazol-3-yl)methylmethanesulfonate

To a solution of 5.8 g (5-trifluoromethyl-isoxazole-3-yl)-methanol in250 mL CH₂Cl₂ was added 12.1 mL triethylamine. Methanesulfonylchloridewas added drop wise at 0-5° C. The mixture was stirred for 30 min. atthis temperature. 50 mL water was added at this temperature. The mixturewas extracted with 50 mL sat. NaCl-solution. The aqueous layer wasre-extracted with CH₂Cl₂ (2×100 mL). The combined org. layer was driedover Na₂SO₄, filtered off and concentrated in vacuo to yield 9.2 g ofthe title compound as a brown oil.

Example BE Preparation of 3-(Azidomethyl)-5-(trifluoromethyl)isoxazole

To a solution of 8.7 g (5-(trifluoromethyl)isoxazol-3-yl)methylmethanesulfonate in 87 mL DMF was added 9.23 g sodium azide. Thereaction mixture was stirred 3 h at RT. 80 mL water was added undercooling. The mixture was extracted with diethyl ether (3×100 mL) and theorganic layers were washed with water (3×100 mL) and then with sat. NaClsolution (1×100 mL). The combined organic layer was dried over Na₂SO₄,filtered off and concentrated in vacuo to yield 6.26 g of the titlecompound as a brown oil.

Example BF Preparation of 5-trifluoromethyl-isoxazol-3-methane amine

To a solution of 6.26 g 3-(azidomethyl)-5-(trifluoromethyl)isoxazole in100 mL 2-propanol were added 9.08 mL triethyl amine and 330 uL1,3-propanedithiol. 2.45 g sodiumhydride were added portion wise andstirred at RT for 16 h. The reaction mixture was concentrated in vacuo.The residue was poured carefully into 180 mL 10% acetic acid and washedwith diethyl ether/heptane mixture 1.1 (3×50 mL) The aqueous layer wasbasified with conc. NaOH to pH=12 (50 mL), saturated with NaCl andextracted with CH₂Cl₂ (3×250 mL). The combined organic layer was driedover Na₂SO₄, filtered off and concentrated in vacuo to yield 3.4 g ofthe title compound as yellow oil; LC-MS (UV peak area/ESI) 97.6%,167.043 (M+H)⁺.

Example BG Preparation of 5-trifluoromethyl-isoxazol-3-methanaminehydrochloride

To a solution of (5-(trifluoromethyl)isoxazol-3-yl)methanamine in 25 mlethanol was added under cooling 5.12 mL 4M-HCl solution in dioxane overa period of 10 min. The ice-bath was removed and 25 ml diethyl ether wasadded drop by drop. Precipitation. Filtered off and washed with diethylether 83×5 mL). Dried in vacuo at 40° C. to yield 2.65 g of the titlecompound as a white solid. MS (EI): 166 (M+H)⁺

Example BH

The starting material 2-cyclopropyl-oxazol-4-methanamine was prepared asfollows.

A mixture of cyclopropanecarboxylic acid amide (5.0 g, 58.74 mmol) and1,3-dichloro-propan-2-one (14.92 g, 117.49 mmol) was heated at 110° C.for 4 h. The mixture was cooled to room temperature and water (75 mL)was added and the mixture was extracted with dichloromethane (3×50 mL).The organic layer was dried over anhydrous sodium sulphate andevaporated in vacuo to get crude residue. After purification via columnchromatography (100-200 silica gel, elution with 2% EtOAc in hexane), 4g of 4-chloromethyl-2-cyclopropyl-oxazole was obtained as a dark brownliquid, 158.0 (M+H)⁺. But it contained impurities. This compound wasused for the next step as such.

To the stirred solution of 4-chloromethyl-2-cyclopropyl-oxazole (4.0 g,25.38 mmol) in dry DMF (30 mL), was added potassium salt of phthalimide(4.7 g, 25.38 mmol) at rt. The resulting mixture was stirred for 24 h atrt and monitored through TLC. After completion of the reaction, water(200 mL) was added and the crude was extracted with ethyl acetate (3×50mL). The combined organic layer was washed with brine, dried overanhydrous sodium sulphate and concentrated under reduced pressure toobtained crude residue which was purified via column chromatography(100-200 silica gel, elution with 20% EtOAc in hexane). 3.5 g of2-(2-cyclopropyl-oxazol-4-ylmethyl)-isoindole-1,3-dione was obtained asa white solid, 269.2 (M+H)⁺, which contained phthalimide. This compoundwas used for the next step as such.

To the suspension of2-(2-cyclopropyl-oxazol-4-ylmethyl)-isoindole-1,3-dione (2.0 g, 7.45mmol) in EtOH (40 mL), was added hydrazine monohydrate (0.435 mL, 8.94mmol) at rt. The resulting mixture was heated to reflux for 5 h andmonitored through TLC. After completion, the reaction mixture wasallowed to rt and the precipitated solid was filtered off and washedwith ethanol (20 mL). The filtrate was concentrated under reducedpressure to get the crude residue which was purified by columnchromatography over de-activated silica (5% triethylamine in hexane,elution with 3% MeOH in DCM). The title compound (3.5 g, 41.6% yield)was obtained as brown sticky liquid, 139.2 (M+H)⁺.

Example BI Preparation of methyl5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinate

5-Bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester(CAN 1211589-51-3; 4.0 g; 12.7 mmol) and 4-chloro-3-methylphenylboronicacid (CAN 161950-10-3; 3.26 g, 19.1 mmol) were combined in DMSO (100 mL)to give a white suspension. To this suspension was added, Na₂CO₃ (4.05g, 38.2 mmol) in water (10 mL) and1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloridedichloromethane complex (1.04 g, 1.27 mmol). The reaction mixture washeated to 80° C. and stirred for 2.5 h, cooled and poured into 200 mLethyl acetate:heptane (1:1) and extracted with H₂O (3×100 mL) and brine(1×150 ml). The aqueous layer was extracted with EtOAc:Heptane (1:1)(1×200 mL). The organic layers were combined, dried with Na₂SO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 70 g, 0% to 100% ethyl acetate in heptane)to yield 4.86 g (90%) of the title compound as light red solid; MS (EI):360.1 (M+H)⁺.

Example BJ Preparation of5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid

Methyl 5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinate(example BI; 4.8 g, 13.3 mmol) and LiOH (0.96 g, 40.0 mmol) werecombined with THF (70 mL), water (14 mL) and methanol (7 mL) to give ayellow suspension. The reaction mixture was stirred for 22 h at roomtemperature, 15 mL water was added and the reaction mixture was heatedto 45° C. and stirred for 3 h. After cooling to room temperature thereaction mixture was poured into 150 mL of 1 M HCl with ice (pH=1) andextracted with ethyl acetate (2×150 mL). The organic layers werecombined, dried with Na₂SO₄, filtrated and concentrated in vacuo. Thecrude material was purified by flash chromatography (silica gel, 70 g,0% to 100% EtOAc in heptane to give 3.8 g (82%) of the title compound asa white crystalline solid; MS (ESI): 346.1 (M+H)⁺.

Example BK Preparation of(6-chloro-4-(3-chloro-4-methylphenyl)-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol

The title compound was synthesized in analogy to Example B using[4-iodo-6-chloro-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol(example A) and B-(3-chloro-4-methylphenyl)-boronic acid, (CAN175883-63-3) as starting materials; LC-MS (UV peak area/ESI) 100%,366.0269 (M+H)⁺.

Example BL Preparation of(4-(3-chloro-4-methylphenyl)-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol

The title compound was synthesized in analogy to Example C using(6-chloro-4-(3-chloro-4-methylphenyl)-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol(example BK) as starting material; LC-MS (UV peak area/ESI) 98.8%,332.0660 (M+H)⁺.

Example BM Preparation of4-(3-chloro-4-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid

The title compound was synthesized in analogy to Example D using(4-(3-chloro-4-methylphenyl)-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol(example BL) as starting material; LC-MS (UV peak area/ESI) 100%,346.0447 (M+H)⁺.

Example BN Preparation of4-(4-chloro-3-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid

The title compound was synthesized in analogy to Examples B to D using[4-iodo-6-chloro-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol(example A) and B-(4-chloro-3-methylphenyl)-boronic acid, (CAN161950-10-3) as starting materials; LC-MS (UV peak area/ESI) 100%,346.0454 (M+H)⁺.

Example BO Preparation of4-(3,4-dimethylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid

The title compound was synthesized in analogy to Examples B to D using[4-iodo-6-chloro-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol(example A) and B-(3,4-dimethylphenyl)-boronic acid, (CAN 55499-43-9) asstarting materials; LC-MS (UV peak area/ESI) 100%, 326.1004 (M+H)⁺.

Example BP Preparation of5-bromo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN1211586-75-2) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine(example AK) as starting materials; LC-MS (UV peak area/ESI) 97%,448.9532 (M−H)⁻.

Example BQ Preparation of5-(3-chloro-4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid

5-Bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN1211586-75-2; 1.5 g; 5.0 mmol) was dissolved in toluene (35 mL) an DMF(2 mL). To this solution was added1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloridedichloromethane complex (204 mg, 250 μmol), followed by3-chloro-4-fluorophenylboronic acid (CAN 144432-85-9; 959 mg, 5.5 mmol)and 2M-Na₂CO₃ (20.0 mL 40.0 mmol). The reaction mixture was heated to90° C. and stirred for 4 h, cooled and poured into 100 mL ice water,acidified with 45 mL 2N—HCl and extracted ethyl acetate. The organiclayers were combined, dried with Na₂SO₄ and concentrated in vacuo. Thecrude material was crystallized from heptane:ethyl acetate (5:1) toyield 1.1 g (63%) of the title compound as light grey solid; LC-MS (UVpeak area/ESI): 97%, 348.0066 (M−H)⁻.

Example BR Preparation of5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid

The title compound was synthesized in analogy to Example BQ using5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN1211586-75-2) and B-(4-chloro-3-fluorophenyl)-boronic acid, (CAN137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 96%,348.0058 (M−H)⁻.

Example BS Preparation of5-(4-ethylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid

The title compound was synthesized in analogy to Example BQ using5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN1211586-75-2) and B-(4-ethylphenyl)-boronic acid, (CAN 63139-21-9) asstarting materials; LC-MS (UV peak area/ESI) 95.8%, 324.0859 (M−H)⁻.

Example BT Preparation of5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid

The title compound was synthesized in analogy to Examples BI to BJ using5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester(CAN 1211589-51-3) and B-(4-chloro-2-fluorophenyl)-boronic acid, (CAN160591-91-3) as starting materials; LC-MS (UV peak area/ESI) 98.8%,348.0061 (M−H)⁻.

Example BU Preparation of5-(4-cyano-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid

The title compound was synthesized in analogy to Example BQ using5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN1211586-75-2) and B-(4-cyanophenyl)-boronic acid, (CAN 126747-14-6) asstarting materials; MS (ESI): 321.2 (M−H).

Example BV Preparation of2-((1-(cyclopropylmethyl)-1H-pyrazol-3-yl)methyl)isoindoline-1,3-dione

To a colorless solution of2-(1H-pyrazol-3-ylmethyl)-1H-Isoindole-1,3(2H)-dione (CAN 95533-75-8;3.66 g, 16.1 mmol) in DMF (80 mL) at 0° C. was added in 4 portionssodium hydride (1.29 g, 32.2 mmol) within 15 min. After warming to roomtemperature the mixture was stirred for 30 min and cyclopropylmethylbromide (21.7 g, 15.6 mL, 161 mmol) in DMF (20 mL) was added within 30min. The mixture was stirred for 22 h at room temperature, poured intoethyl acetate (200 mL) and extracted with water (3×100 mL). Water phaseswere washed with ethyl acetate (200 mL), organic phases were combined,dried with MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, 80 g, 0% to 100% EtOAc inheptane) and finally by preparative HPLC to give 1.63 g (36%) of thetitle compound as a white solid; MS (EI): 282.2 (M+H)⁺.

Example BW Preparation of(1-(cyclopropylmethyl)-1H-pyrazol-3-yl)methanamine

To a colorless solution of2-((1-(cyclopropylmethyl)-1H-pyrazol-3-yl)methyl)isoindoline-1,3-dione(example BV; 400 mg, 1.42 mmol) in THF (10 mL) and ethanol (5 mL) wasadded hydrazine hydrate (0.62 g, 0.60 mL, 12.3 mmol). The whitesuspension was stirred for 20 h at room temperature, diluted witht-butylmethyl ether (50 mL) and phtalyl hydrazide was removed byfiltration. The filtrate was concentrated in vacuo and the crudematerial was purified by flash chromatography (amino phase, 12 g, 0% to100% ethyl acetate in heptane) to yield 197 mg (92%) of the titlecompound as a light yellow oil; MS (EI): 152.1 (M+H)⁺.

Example BX Preparation of5-(3,4-difluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid

The title compound was synthesized in analogy to Example BQ using5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN1211586-75-2) and B-(3,4-difluorophenyl)-boronic acid, (CAN 168267-41-2)as starting materials.

Example BY Preparation of 5-bromo-6-cyclobutoxynicotinic acid

5-Bromo-6-chloronicotinic acid (CAN 29241-62-1, 2.0 g, 8.46 mmol) wasdissolved in DMSO (20.0 mL). Cyclobutanol (793 mg, 857 μL, 11.0 mmol)and potassium hydroxide powder (1.42 g, 25.4 mmol) were added and themixture was stirred at room temperature overnight. Water (20 mL) wasadded and the mixture was acidified (under ice-water bath cooling) with37% HCL in water (pH=2). The suspension was filtered, washed with waterand the solid was dried to yield 1.88 g (82%) of the title compound as awhite solid; MS (ESI): 270.2 (M−H)⁻.

Example BZ Preparation of 6-cyclobutoxy-5-(3,4-difluorophenyl)nicotinicacid

The title compound was synthesized in analogy to Example BQ using6-cyclobutoxy-5-(3,4-difluorophenyl)nicotinic acid (example BY) andB-(3,4-difluorophenyl)-boronic acid (CAN 168267-41-2) as startingmaterials; MS (ESI): 304.2 (M−H)⁻.

Example CA Preparation of 5-(4-chlorophenyl)-6-cyclobutoxynicotinic acid

The title compound was synthesized in analogy to Example BQ using5-bromo-6-cyclobutoxy-5-nicotinic acid (example BY) andB-(4-chlorophenyl)-boronic acid (CAN 1679-18-1) as starting materials;MS (ESI): 302.2 (M−H)⁻.

Example CB Preparation of5-(4-chloro-3-fluorophenyl)-6-cyclobutoxynicotinic acid

The title compound was synthesized in analogy to Example BQ using5-bromo-6-cyclobutoxy-5-nicotinic acid (example BY) andB-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as startingmaterials; MS (ESI): 320.2 (M−H)⁻.

Example CC Preparation of5-(4-chloro-3-methylphenyl)-6-cyclobutoxynicotinic acid

The title compound was synthesized in analogy to Example BQ using5-bromo-6-cyclobutoxy-nicotinic acid (example BY) andB-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as startingmaterials; MS (ESI): 316.2 (M−H)⁻.

Example CD Preparation of6-(cyclopropylmethoxy)-5-(3,4-difluorophenyl)nicotinic acid

The title compound was synthesized in analogy to Example BQ using5-bromo-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CAN912454-38-7) and B-(3,4-difluorophenyl)-boronic acid, (CAN 168267-41-2)as starting materials; MS (ESI): 304.2 (M−H)⁻.

Example CE Preparation of5-(3,4-difluorophenyl)-6-(2-methoxyethoxy)nicotinic acid

The title compound was synthesized in analogy to Example BQ using5-bromo-6-(2-methoxyethoxy)-3-pyridinecarboxylic acid (CAN 912454-34-3)and B-(3,4-difluorophenyl)-boronic acid, (CAN 168267-41-2) as startingmaterials; MS (ESI): 308.3 (M−H)⁻.

Example CF Preparation of5-(4-chloro-3-fluorophenyl)-6-(2-methoxyethoxy)nicotinic acid

The title compound was synthesized in analogy to Example BQ using5-bromo-6-(2-methoxyethoxy)-3-pyridinecarboxylic acid (CAN 912454-34-3)and B-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) asstarting materials; LC-MS (UV peak area/ESI) 100%, 324.0456 (M−H)⁻.

Example CG Preparation of5-(4-chloro-3-methylphenyl)-6-(2-methoxyethoxy)nicotinic acid

The title compound was synthesized in analogy to Example BQ using5-bromo-6-(2-methoxyethoxy)-3-pyridinecarboxylic acid (CAN 912454-34-3)and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) asstarting materials; LC-MS (UV peak area/ESI) 94%, 322.0842 (M+H)⁺.

Example CH Preparation of5-benzo[1,2,5]oxadiazol-5-yl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid

The title compound was synthesized in analogy to Example BQ using5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN1211586-75-2) and B-2,1,3-benzoxadiazol-5-yl-boronic acid, (CAN426268-09-9) as starting materials; LC-MS (UV peak area/ESI) 48%, 338.0(M−H)⁻.

Example CI Preparation of5-(4-chlorophenyl)-6-(2-hydroxyethoxy)nicotinic acid

To a solution of ethane-1,2-diol (301 mg, 270 μA, 4.84 mmol) in driedDMF (6 mL) was added sodium hydride (232 mg, 4.84 mmol) and the reactionmixture was stirred at room temperature for 15 minutes. The resultingsolution was added slowly to a solution of6-chloro-5-(4-chlorophenyl)-3-pyridinecarboxylic acid (CAN 1012792-56-1;0.590 g, 2.2 mmol) in dried DMF (6 mL) and stirred at 80° C. for 4 h.More sodium hydride (106 mg, 2.2 mmol) was added and at room temperatureand stirring at 80° C. commenced for another 2 h. Water was added andDMF was evaporated. The residue was dissolved in water; acidified with3M HCl to pH 3. The suspension was filtered; the filter cake was washedwith water and dried under high vacuo. The crude material was purifiedby flash chromatography (ReproFlash Acidosil-S, 50 g, 50% to 100%ethylacetate in heptane) to give 0.27 g (41%) of the title compound as awhite solid; MS (ESI): 292.1 (M−H)⁻.

Example CJ Preparation of(R)-5-(4-chlorophenol)-6-(tetrahydrofuran-3-yloxy)nicotinic acid

The title compound was synthesized in analogy to Example CI using6-chloro-5-(4-chlorophenyl)-3-pyridinecarboxylic acid (CAN 1012792-56-1)and (3R)-tetrahydro-3-furanol (CAN 86087-24-3) as starting materials;LC-MS (UV peak area/ESI) 88.1%, 318.1 (M−H)⁻.

Example CK Preparation of5-(4-chloro-phenyl)-6-(tetrahydro-furan-3-ylmethoxy)-nicotinic acid

The title compound was synthesized in analogy to Example CI using6-chloro-5-(4-chlorophenyl)-3-pyridine carboxylic acid (CAN1012792-56-1) and tetrahydro-3-furanmethanol (CAN 15833-61-1) asstarting materials; LC-MS (UV peak area/ESI) 91.6%, 334.0833 (M+H)⁺.

Example 1 Preparation of4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (3-methoxy-isoxazol-5-ylmethyl)-amide

4-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (100 mg, 0.3 mmol, example D) was dissolved in dimethylformamide (4mL). To this stirred solution under argon was added in sequence2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(107 mg, 0.3 mmol), N,N-diisopropyl ethyl amine (0.26 mL, 1.5 mmol) and3-methoxy-5-isoxazolemethanamine hydrochloride (55 mg, 0.3 mmol). Themixture was shaken for 16 h at room temperature, solvent was removed invacuo (45° C.) and the residue was digested with dichloromethane (5 mL)and 2N NaOH (1.5 mL) for 5 min. The mixture was absorbed onto 10 gChemElut (Varian) and eluted with dichloromethane (70 mL). Solvent wasevaporated and the brown, oily residue (160 mg) was purified by gradientchromatography on silica with ethyl acetate/n-heptane to give the titlecompound as a white solid (122 mg, 92%), LC-MS (UV peak area/ESI) 93%,442.0769 (M+H)⁺.

Example 2 Preparation of4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (3-isopropyl-isoxazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example D) and 3-(1-methylethyl)-5-isoxazolemethanamine asstarting materials; LC-MS (UV peak area/ESI) 100%, 454.1134 (M+H)⁺.

Example 3 Preparation of4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (3-ethyl-isoxazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example D) and 3-ethyl-5-isoxazolemethanamine as startingmaterials; LC-MS (UV peak area/ESI) 100%, 440.0985 (M+H)⁺.

Example 4 Preparation of4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (1-propyl-1H-pyrazol-3-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example D) and 1-propyl-1H-pyrazole-3-methanamine (CAS RegistryNo. 1006333-47-6) as starting materials; LC-MS (UV peak area/ESI) 100%,453.1306 (M+H)⁺.

Example 5 Preparation of5-(4-chloro-phenyl)-N-(3-methoxy-isoxazol-5-ylmethyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid(CAS Registry No. 1018782-82-5) and 3-methoxy-5-isoxazolemethanaminehydrochloride as starting materials, LC-MS (UV peak area/ESI) 100%,442.079 (M+H)⁺.

Example 6 Preparation of4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (2-isopropyl-thiazol-4-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example D) and 2-(1-methylethyl)-4-thiazole-methanamine, asstarting materials; LC-MS (UV peak area/ESI) 80%, 470.902 (M+H)⁺.

Example 7 Preparation of5-(4-chloro-phenyl)-N-(2-ethyl-thiazol-4-ylmethyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid(CAS Registry No. 1018782-82-5) and 2-ethyl-4-thiazolemethanamine asstarting materials; LC-MS (UV peak area/ESI) 98%, 456.074 (M+H)⁺.

Example 8 Preparation of5-(4-chloro-phenyl)-N-(2-isopropyl-thiazol-4-ylmethyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid(CAS Registry No. 1018782-82-5) and2-(1-methylethyl)-4-thiazolemethanamine as starting materials, LC-MS (UVpeak area/ESI) 98%, 470.090 (M+H)⁺.

Example 9 Preparation of5-(4-chloro-phenyl)-N-(2-propyl-thiazol-4-ylmethyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid(CAS Registry No. 1018782-82-5) and 2-propyl-4-thiazolemethanamine asstarting materials, LC-MS (UV peak area/ESI) 99%, 470.090 (M+H)⁺.

Example 10 Preparation of5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-(2-ethyl-thiazol-4-ylmethyl)-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CASRegistry No. 1018782-76-7) and 2-ethyl-4-thiazolemethanamine as startingmaterials, LC-MS (UV peak area/ESI) 99%, 428.119 (M+H)⁺.

Example 11 Preparation of5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-(2-propyl-thiazol-4-ylmethyl)-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CASRegistry No. 1018782-76-7) and 2-propyl-4-thiazolemethanamine asstarting materials, LC-MS (UV peak area/ESI) 99%, 442.134 (M+H)⁺.

Example 12 Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-N-(5-trifluoromethyl-[1,2,4]oxadiazol-3-ylmethyl)-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CASRegistry No. 1018782-82-5) andC-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-methylamine hydrochloride(example AI), LC-MS (UV peak area/ESI) 93%, 479.035 (M−H)⁻.

Example 13 Preparation of4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid(5-cyclopropyl-[1,2,4]oxadiazol-3-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid(example T) and [(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]amine (CASRegistry No. 1082420-52-7), LC-MS (UV peak area/ESI) 100%, 426.132(M+H)⁺.

Example 14 Preparation of5-(4-chloro-phenyl)-N-(1-propyl-1H-pyrazol-3-ylmethyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CASRegistry No. 1018782-82-5) and 1-propyl-1H-pyrazole-3-methanamine (CASRegistry No. 1006333-47-6) as starting materials, LC-MS (UV peakarea/ESI) 96%, 453.29 (M+H)⁺.

Example 15 Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-N-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CASRegistry No. 1018782-82-5) andC-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride(CAS registry No. 944905-93-5; example AK) as starting materials, LC-MS(UV peak area/ESI) 100%, 479.0355 (M+H)⁺.

Example 16 Preparation of4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid (example W) andC-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride(CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS(UV peak area/ESI) 100%, 482.0446 (M+H)⁺.

Example 17 Preparation of4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid(3-cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid(example T) and (3-cyclopropyl-1,2,4-oxadiazol-5-yl)methane amine (CASRegistry No. 428507-31-7) as starting materials; LC-MS (UV peakarea/ESI) 100%, 426.1324 (M+H)⁺.

Example 18 Preparation of4-(4-chlorophenyl)-5-(cyclopropylmethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)picolinamide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(cyclopropylmethyloxy)-pyridine-2-carboxylic acid(example H) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylaminehydrochloride (CAS registry No. 944905-93-5; example AK) as startingmaterials; LC-MS (UV peak area/ESI) 100%, 453.0924 (M+H)⁺.

Example 19 Preparation of4-(4-chlorophenyl)-N-((5-methylisoxazol-3-yl)methyl)-5-(2,2,2-trifluoro-ethoxy)picolinamide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example D) and 5-methyl-3-isoxazolemethanamine (CAS registry No.154016-48-5) as starting materials; LC-MS (UV peak area/ESI) 100%,426.0822 (M+H)⁺.

Example 20 Preparation of5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridazine-3-carboxylic acid(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridazine-3-carboxylic acid(example P) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylaminehydrochloride (CAS registry No. 944905-93-5; example AK) as startingmaterials; LC-MS (UV peak area/ESI) 100%, 454.0888 (M+H)⁺.

Example 21 Preparation of4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid(example T) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylaminehydrochloride (CAS registry No. 944905-93-5; example AK) as startingmaterials; LC-MS (UV peak area/ESI) 100%, 454.0901 (M+H)⁺.

Example 22 Preparation of6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example AF) andC-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride(CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS(UV peak area/ESI) 100%, 479.0355 (M−H)⁻.

Example 23 Preparation of5-(4-chlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxamide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (example M) and 3-methoxy-5-isoxazole-methanamine hydrochloride asstarting materials, 443.1 (M+H)⁺.

Example 24 Preparation of(S)-5-(4-chlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-6-(1,1,1-trifluoropropan-2-yloxy)pyridazine-3-carboxamide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridazine-3-carboxylicacid (example AG) and 3-methoxy-5-isoxazole-methanamine hydrochloride asstarting materials, 457.1 (M+H)⁺.

Example 25 Preparation of4-(3,4-dichlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)pyrimidine-2-carboxamide

The title compound was synthesized in analogy to Example 1, using4-(3,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid (example AA) and 3-methoxy-5-isoxazolemethanamine hydrochloride asstarting materials, 477.0 (M+H)⁺.

Example 26 Preparation ofN-(4-Chloro-1-methyl-1H-pyrazol-3-ylmethyl)-5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CASRegistry No. 1018782-82-5) and[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]amine (CAS Registry No.1017785-44-2) as starting materials; LC-MS (UV peak area/ESI) 100%,458.0604 (M+H)⁺.

Example 27 Preparation of4-(4-chlorophenyl)-N-((5-isopropylisoxazol-3-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example D) and 5-(1-methylethyl)-3-isoxazolemethanamine (CASRegistry No. 154016-49-6) as starting materials; LC-MS (UV peakarea/ESI) 98.5%, 454.1122 (M+H)⁺.

Example 28 Preparation of4-(4-chlorophenyl)-N-((5-cyclopropylisoxazol-3-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example D) and 5-cyclopropyl-3-isoxazolemethanamine (CAS RegistryNo. 1060817-49-3) as starting materials; LC-MS (UV peak area/ESI) 98.6%,452.0979 (M+H)⁺.

Example 29 Preparation of(S)-6-(4-chlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxamide

The title compound was synthesized in analogy to Example 1, using(S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylicacid (example AG) and 3-methoxy-5-isoxazolemethanamine hydrochloride asstarting materials, 455.1 (M+H)⁺.

Example 30 Preparation of5-(4-chloro-phenyl)-N-(5-cyclopropyl-isoxazol-3-ylmethyl)-6-cyclopropyl-methoxy-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-cyclopropylmethoxy-nicotinic acid (CAS RegistryNo. 1018782-76-7) and 5-aminomethyl-3 cyclopropylisoxazole (CAS registryNo. 851434-73-6) as starting materials, 424.1 (M+H)⁺.

Example 31 Preparation of5-(4-chlorophenyl)-N-((5-isopropylisoxazol-3-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CASRegistry No. 1018782-82-5) and 5-(1-methylethyl)-3-isoxazolemethanamine(CAS Registry No. 154016-49-6) as starting materials, 454.1 (M+H)⁺.

Example 32 Preparation of5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-N-((5-isopropylisoxazol-3-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-cyclopropylmethoxy-nicotinic acid (CAS RegistryNo. 1018782-76-7) and 5-(1-methylethyl)-3-isoxazolemethanamine (CASRegistry No. 154016-49-6) as starting materials, 426.2 (M+H)⁺.

Example 33 Preparation of4-(4-chlorophenyl)-N-((3-cyclopropylisoxazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example D) and 3-cyclopropyl-5-isoxazolemethanamine (CAS RegistryNo. 851434-73-6) as starting materials; LC-MS (UV peak area/ESI) 97.6%,452.0973 (M+H)⁺.

Example 34 Preparation of(S)-5-(4-chlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinamide

The title compound was synthesized in analogy to Example 1, using(S)-5-(4-chlorophenyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinic acid(Example AO) and 3-methoxy-5-isoxazolemethanamine hydrochloride asstarting materials. MS: 456.1 (M+H)⁺.

Example 35 Preparation of(S)-4-(4-chlorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxamide

The title compound was synthesized in analogy to Example 1, using(S)-4-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxylicacid (Example AQ) andC-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride(CAN 944905-93-5; example AK) as starting materials. MS: 496.1 (M+H)⁺.

Example 36 Preparation of(S)-6-(4-chlorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxamide

The title compound was synthesized in analogy to Example 1, using(S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylicacid (example AG) andC-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride(CAN 944905-93-5; example AK) as starting materials. MS: 494.0 (M−H)⁻.

Example 37 Preparation of(S)-4-(4-chlorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-5-(1,1,1-trifluoropropan-2-yloxy)picolinamide

The title compound was synthesized in analogy to Example 1, using(S)-4-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)picolinic acid(example AR) and 3-methoxy-5-isoxazolemethanamine hydrochloride asstarting materials. MS: 456.1 (M+H)⁺.

Example 38 Preparation of(S)-5-(4-chlorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinamide

The title compound was synthesized in analogy to Example 1, using(S)-5-(4-chlorophenyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinic acid(Example AO) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylaminehydrochloride (CAS registry No. 944905-93-5; example AK) as startingmaterials; MS: 493.1 (M−H)⁻.

Example 39 Preparation of4-(4-chlorophenyl)-N-((5-isopropyl-1,2,4-oxadiazol-3-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example D) and 5-(1-methylethyl)-1,2,4-oxadiazole-3-methanamine,(CAN 936940-30-6) as starting materials; LC-MS (UV peak area/ESI) 100%,455.1092 (M+H)⁺.

Example 40 Preparation of4-(4-chlorophenyl)-N-((3-isopropyl-1,2,4-oxadiazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example D) and 3-(1-methylethyl)-1,2,4-oxadiazole-5-methanamine(CAN 936940-67-9) as starting materials, LC-MS (UV peak area/ESI) 97.2%,455.1099 (M+H)⁺.

Example 41 Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (5-cyclopropyl-[1,2,4]oxadiazol-3-ylmethyl)-amide

To a stirred solution of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (example M, 100 mg, 0.300 mmol) in dimethylformamide (4 mL, dried),was added 4-methylmorpholine (CAS No. 109-02-4, 0.09 mL 0.901 mmol),HBTU (CAS No. 94790-37-1, 171 mg, 0.450 mmol),5-cyclopropyl-[1,2,4]oxadiazol-3-methanamine hydrochloride (Chembridge,MFCD09864586, 52 mg, 0.300 mmol) at rt and this mixture was stirred for12 h at rt. Volatile were removed under reduced pressure and the residuewas extracted with ethyl acetate. The combined organic layer was washedwith aq. NaHCO₃ soln, brine and concentrated to afford the crude residuewhich was purified by column chromatography (100-200 silica gel, elutionwith ethyl acetate/hexane). The title compound (91 mg, 66.0% yield) wasobtained as a white solid; LC-MS (UV peak area/ESI) 96.8%, 454.6 (M+H)⁺.

Example 42 Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (5-isopropyl-isoxazol-3-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (example M) and 5-(1-methylethyl)-3-isoxazolemethanamine (CASRegistry No. 154016-49-6) as starting materials; LC-MS (UV peakarea/ESI) 99.1%, 455.2 (M+H)⁺.

Example 43 Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (3-isopropyl-isoxazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (example M) and 3-(1-methylethyl)-5-isoxazolemethanamine (CAN.543713-30-0) as starting materials, LC-MS (UV peak area/ESI) 100.0%,455.2 (M+H)⁺.

Example 44 Preparation of4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid (3-isopropyl-isoxazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid (example W) and 3-(1-methylethyl)-5-isoxazolemethanamine (CAN543713-30-0) as starting materials; LC-MS (UV peak area/ESI) 98.43%,455.0 (M+H)⁺.

Example 45 Preparation of4-(4-chlorophenyl)-5-(2,2,2-trifluoroethoxy)-N-((5-(trifluoromethyl)isoxazol-3-yl)methyl)picolinamide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example D) and 5-trifluoromethyl-isoxazol-3-methanaminehydrochloride (example BG) as starting materials; LC-MS (UV peakarea/ESI) 100%, 480.0532 (M+H)⁺.

Example 46 Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (example M) andC-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride(CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS(UV peak area/ESI) 100.0%, 482.0 (M+H)⁺.

Example 47 Preparation of6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (3-cyclopropyl-isoxazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41, using6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example AF) and 3-cyclopropyl-5-isoxazolemethanamine (CAN851434-73-6) as starting materials, LC-MS (UV peak area/ESI) 99.6%,452.2 (M+H)⁺.

Example 48 Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (3-cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (example M) and 3-cyclopropyl-1,2,4-oxadiazole-5-methanamine (CASRegistry No. 428507-31-7) as starting materials; LC-MS (UV peakarea/ESI) 97.6%, 454.2 (M+H)⁺.

Example 49 Preparation of5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (3-cyclopropyl-isoxazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (example M) and 3-cyclopropyl-5-isoxazolemethanamine (CAN851434-73-6) as starting materials, LC-MS (UV peak area/ESI) 92.9%,453.2 (M+H)⁺.

Example 50 Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-N-(5-trifluoromethyl-isoxazol-3-ylmethyl)-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAN1018782-82-5) and 5-trifluoromethyl-isoxazol-3-methanamine hydrochloride(example BF) as starting materials; MS: 478.0 (M+H)⁺.

Example 51 Preparation of5-(4-chlorophenyl)-6-cyclopropylmethoxy-N-(5-isopropyl-[1,2,4]oxadiazol-3-yl)methyl)-nicotinamide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-(cyclopropylmethoxy)-3-pyridine carboxylic acid(CAN 1018782-76-7) and 5-(1-methylethyl)-1,2,4-oxadiazole-3-methanamine,(CAN 936940-30-6) as starting materials, MS 472.2 (M+H)⁺.

Example 52 Preparation of6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(2-isopropyl-thiazol-4-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41, using6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(example AW) and 2-(1-methylethyl)-4-thiazole-methanaminedihydrochloride (CAN 1171981-10-4) as starting materials, LC-MS (peakarea/EIC) 97.9%, 442.0 (M+H)⁺.

Example 53 Preparation of6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (5-isopropyl-isoxazol-3-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41, using6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (example AF) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAN154016-49-6) as starting materials; LC-MS (UV peak area/ESI) 97.1%,454.6 (M+H)⁺.

Example 54 Preparation ofN-((2-tert-butylthiazol-4-yl)methyl)-4-(4-chlorophenyl)-5-(cyclopropylmethoxy)picolinamide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(cyclopropylmethyloxy)-pyridine-2-carboxylic acid(example H) and 2-(1,1-dimethylethyl)-4-thiazolemethanamine (CAN937656-81-0) as starting materials; LC-MS (UV peak area/ESI) 100%,456.1491 (M+H)⁺.

Example 55 Preparation of6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(5-isopropyl-isoxazol-3-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41 using6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(example AW) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAN154016-49-6) as starting materials, LC-MS (peak area/EIC) 98.2%, 426.4(M+H)⁺.

Example 56 Preparation of6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(2-cyclopropyl-oxazol-4-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41, using6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(example AW) and 2-cyclopropyl-4-oxazolmethanamine (example BH) asstarting materials, LC-MS (UV peak area/ESI) 97.6%, 424.0 (M+H)⁺.

Example 57 Preparation of6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(2-cyclopropyl-thiazol-4-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41 using6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(example AW) and 2-cyclopropyl-4-thiazolemethanamine (CAN. 1083299-53-9)as starting materials, LC-MS (UV peak area/ESI) 95.5%, 440.2 (M+H)⁺.

Example 58 Preparation of6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(5-trifluoromethyl-isoxazol-3-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41 using6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(example AW) and 5-trifluoromethyl-isoxazol-3-methanamine hydrochloride(example BF) as starting materials, LC-MS (UV peak area/ESI) 97.8%,452.4 (M+H)⁺.

Example 59 Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-N-(3-trifluoromethyl-isoxazol-5-ylmethyl)-nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CASRegistry No. 1018782-82-5) and 3-trifluoromethyl-isoxazol-5-methanamine(example BA) as starting materials; MS: 478.0 (M+H)⁺.

Example 60 Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (3-trifluoromethyl-isoxazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (example M) and 3-trifluoromethyl-isoxazol-5-methanamine (exampleBA) as starting materials; MS: 480.0 (M)⁺.

Example 61 Preparation of4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid (3-trifluoromethyl-isoxazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylicacid (example AA) and 3-trifluoromethyl-isoxazol-5-methanamine (exampleBA) as starting materials; MS: 481.0 (M+H)⁺.

Example 62 Preparation of4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid(3-trifluoromethyl-isoxazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 1, using4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid(example T) and 3-trifluoromethyl-isoxazol-5-methanamine (example BA) asstarting materials; MS: 453.1 (M+H)⁺.

Example 63 Preparation of6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(2-tert-butyl-thiazol-4-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41, using6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(example AW) and 2-(1,1-dimethylethyl)-4-thiazolemethanamine (CAN937656-81-0) as starting materials; LC-MS (UV peak area/ESI) 97.7%,456.0 (M+H)⁺.

Example 64 Preparation of6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (3-isopropyl-isoxazol-5-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41 using6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-2-pyridine carboxylicacid (example AF) and 3-(1-methylethyl)-5-isoxazolemethanamine (CAN543713-30-0) as starting materials; LC-MS (UV peak area/ESI) 100.0%,454.4 (M+H)⁺.

Example 65 Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (2-tert-butyl-thiazol-4-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41 using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (example M) and 2-(1,1-dimethylethyl)-4-thiazolemethanamine (CASRegistry No. 937656-81-0) as starting materials; LC-MS (UV peakarea/ESI) 99.1%, 485.2 (M+H)⁺.

Example 66 Preparation of5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-(5-trifluoromethyl-isoxazol-3-ylmethyl)-nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CAN1018782-76-7) and 5-trifluoromethyl-isoxazol-3-methanamine (example BF)as starting materials; LC-MS (UV peak area/ESI) 98%, 452.0975 (M+H)⁺.

Example 67 Preparation of5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (5-trifluoromethyl-isoxazol-3-ylmethyl)-amide

The title compound was synthesized in analogy to Example 41 using5-(4-chlorophenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylicacid (example M) and 5-trifluoromethyl-isoxazol-3-methanamine (exampleBF) as starting materials; LC-MS (UV peak area/ESI), 94.3%, 481.3(M+H)⁺.

Example 68 Preparation of(S)-4-(4-chlorophenyl)-N-((3-(trifluoromethyl)isoxazol-5-yl)methyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxamide

The title compound was synthesized in analogy to Example 1 using(S)-4-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxylicacid (example AQ) and 3-trifluoromethyl-isoxazol-5-methanamine (exampleBA) as starting materials; LC-MS (UV peak area/ESI) 100%, 495.0965(M+H)⁺.

Example 69 Preparation of(S)-6-(4-chlorophenyl)-N-(pyridin-2-ylmethyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxamide

The title compound was synthesized in analogy to Example 1 using(S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylicacid (example AH) and 2-pyridinemethanamine (CAN 3731-51-9) as startingmaterials; MS (ESI): 437.1 (M+H)⁺.

Example 70 Preparation of4-(4-chlorophenyl)-N-((2-cyclopropyloxazol-4-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide

The title compound was synthesized in analogy to Example 1 using4-(4-chlorophenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid(example D) and 2-cyclopropyl-oxazol-4-methanamine (example BH) asstarting materials; LC-MS (UV peak area/ESI) 96.5%, 452.0987 (M+H)⁺.

Example 71 Preparation of5-(4-chloro-3-methylphenyl)-N-((2-cyclopropylthiazol-4-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid(example BJ) and 2-cyclopropyl-4-thiazolemethanamine (CAN 1083299-53-9)as starting materials; LC-MS (UV peak area/ESI) 95.4%, 482.09 (M+H)⁺.

Example 72 Preparation of5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid(example BJ) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine(example AK) as starting materials; LC-MS (UV peak area/ESI) 100%,493.0523 (M+H)⁺.

Example 73 Preparation of4-(3-chloro-4-methylphenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide

The title compound was synthesized in analogy to Example 1 using4-(3-chloro-4-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid(example BM) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) asstarting materials; LC-MS (UV peak area/ESI) 100%, 456.0934 (M+H)⁺.

Example 74 Preparation of4-(4-chloro-3-methylphenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide

The title compound was synthesized in analogy to Example 1 using4-(4-chloro-3-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid(example BN) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) asstarting materials; LC-MS (UV peak area/ESI) 100%, 456.0938 (M+H)⁺.

Example 75 Preparation of4-(3,4-dimethylphenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide

The title compound was synthesized in analogy to Example 1 using4-(3,4-dimethylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (exampleBO) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) as startingmaterials; LC-MS (UV peak area/ESI) 100%, 436.1476 (M+H)⁺.

Example 76 Preparation of4-(4-chloro-3-methylphenyl)-N-((2-cyclopropylthiazol-4-yl)methyl)-5-(2,2,2-trifluoroethoxy)picolinamide

The title compound was synthesized in analogy to Example 1 using4-(4-chloro-3-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid(example BN) and 2-cyclopropyl-4-thiazolemethanamine (CAN 1083299-53-9)as starting materials; LC-MS (UV peak area/ESI) 100%, 482.0911 (M+H)⁺.

Example 77 Preparation of4-(4-chloro-3-methylphenyl)-5-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)picolinamide

The title compound was synthesized in analogy to Example 1 using4-(4-chloro-3-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid(example BN) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine(example AK) as starting materials; LC-MS (UV peak area/ESI) 100%,493.0499 (M+H)⁺.

Example 78 Preparation of4-(3,4-dimethylphenyl)-5-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)picolinamide

The title compound was synthesized in analogy to Example 1 using4-(3,4-dimethylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (exampleBO) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; LC-MS (UV peak area/ESI) 100%, 475.1211 (M+H)⁺.

Example 79 Preparation of5-p-tolyl-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

5-Bromo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide(example BP; 100 mg, 223 μmol), p-tolylboronic acid (CAN 5720-05-8; 33mg, 243 μmol),1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloridedichloromethane complex (4 mg, 5.27 μmol) and Na₂CO₃ (35 mg, 330 μmol)were combined with tetrahydrofuran (5 mL) and water (1.5 mL). Thereaction mixture was heated to 90° C., stirred for 15 h, cooled down andpoured into 25 mL H₂O. The mixture was extracted with ethyl acetate(2×25 mL). The organic layers were combined, washed with brine (1×25mL), dried with MgSO₄ and concentrated in vacuo. The crude material waspurified twice by flash chromatography (silica gel, 20 g, 0% to 40%ethyl acetate in hexanes) to give 48 mg (46%) of the title compound as alight yellow solid; MS (ESI): 459.090 (M−H)⁻.

Example 80 Preparation of5-(3-chloro-4-methylphenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 83 using5-bromo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide(example BP) and B-(3-chloro-4-methylphenyl)-boronic acid, (CAN175883-63-3) as starting materials; LC-MS (UV peak area/ESI) 100%,493.0516 (M+H)⁺.

Example 81 Preparation of5-(3-chloro-4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(3-chloro-4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid(example BQ) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine(example AK) as starting materials; LC-MS (UV peak area/ESI) 97.1%,497.0259 (M−H)⁻.

Example 82 Preparation of5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid(example BR) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine(example AK) as starting materials; LC-MS (UV peak area/ESI) 98.8%,497.0260 (M+H)⁺.

Example 83 Preparation of5-(4-ethylphenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-ethylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BS)and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; LC-MS (UV peak area/ESI) 100%, 473.1054 (M−H)⁻.

Example 84 Preparation of5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid(example BT) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine(example AK) as starting materials; LC-MS (UV peak area/ESI) 98.6%,497.0254 (M−H)⁻.

Example 85 Preparation of5-(2,3-dihydro-1H-inden-5-yl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 83 using5-bromo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide(example BP) and B-(2,3-dihydro-1H-inden-5-yl)-boronic acid (CAN196861-31-1) as starting materials; LC-MS (UV peak area/ESI) 100%,485.1016 (M−H)⁻.

Example 86 Preparation of5-(4-chloro-3-fluorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid(example BR) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) asstarting materials; LC-MS (UV peak area/ESI) 100%, 458.0537 (M−H)⁻.

Example 87 Preparation of5-(4-cyanophenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-cyanophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BU)and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; MS (ESI): 470.2 (M−H)⁻.

Example 88 Preparation of5-(4-chlorophenyl)-N-((1-(cyclopropylmethyl)-1H-pyrazol-3-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAN1018782-82-5) and (1-(cyclopropylmethyl)-1H-pyrazol-3-yl)methanamine(example BW) as starting materials, MS (EI) 465.3 (M+H)⁺.

Example 89 Preparation of5-(3,4-difluorophenyl)-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(3,4-difluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (exampleBX) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; MS (ESI): 483.2 (M+H)⁺.

Example 90 Preparation of5-(4-chlorophenyl)-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAN1018782-82-5) and 3-methyl-1,2,4-oxadiazole-5-methanamine (CAN90928-92-0) as starting materials; LC-MS (UV peak area/ESI) 100%,425.0644 (M−H)⁻.

Example 91 Preparation of6-cyclobutoxy-5-(3,4-difluorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using6-cyclobutoxy-5-(3,4-difluorophenyl)nicotinic acid (example BZ) and3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; LC-MS (UV peak area/ESI) 98.0%, 455.1 (M+H)⁺.

Example 92 Preparation of5-(4-chlorophenyl)-6-cyclobutoxy-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chlorophenyl)-6-cyclobutoxy-nicotinic acid (example CA) and3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; LC-MS (UV peak area/ESI) 92.8%, 451.1 (M−H)⁻.

Example 93 Preparation of5-(4-chloro-3-fluorophenyl)-6-cyclobutoxy-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-3-fluorophenyl)-6-cyclobutoxy-nicotinic acid (example CB)and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; LC-MS (UV peak area/ESI) 90.1%, 471.1 (M+H)⁺.

Example 94 Preparation of5-(4-chloro-3-methylphenyl)-6-cyclobutoxy-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-3-methylphenyl)-6-cyclobutoxy-nicotinic acid (example CC)and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; LC-MS (UV peak area/ESI) 93.8%, 467.1 (M+H)⁺.

Example 95 Preparation of6-(cyclopropylmethoxy)-5-(3,4-difluorophenyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using6-(cyclopropylmethoxy)-5-(3,4-difluorophenyl)-nicotinic acid (exampleCD) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; LC-MS (UV peak area/ESI) 100.0%, 455.1 (M+H)⁺.

Example 96 Preparation of5-(3,4-difluorophenyl)-6-(2-methoxyethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(3,4-difluorophenyl)-6-(2-methoxyethoxy)-nicotinic acid (example CE)and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; LC-MS (UV peak area/ESI) 87.6%, 459.1 (M+H)⁺.

Example 97 Preparation of5-(4-chloro-3-fluorophenyl)-6-(2-methoxyethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-3-fluorophenyl)-6-(2-methoxyethoxy)-nicotinic acid (exampleCF) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; LC-MS (UV peak area/ESI) 100%, 473.0662 (M−H)⁻.

Example 98 Preparation of5-(4-chloro-3-methylphenyl)-6-(2-methoxyethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-3-methylphenyl)-6-(2-methoxyethoxy)nicotinic acid (exampleCG) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; LC-MS (UV peak area/ESI) 100%, 469.0893 (M−H)⁻.

Example 99 Preparation of5-(3,4-difluorophenyl)-N-((3-methoxyisoxazol-5-yl)methyl)-6-(2,2,2-trifluoroethoxy)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(3,4-difluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (exampleBX) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) as startingmaterials; LC-MS (UV peak area/ESI) 84%, 407.9815 (M+H)⁺.

Example 100 Preparation of5-Benzo[1,2,5]oxadiazol-5-yl-6-(2,2,2-trifluoro-ethoxy)-N-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl-methyl)-nicotinamide

The title compound was synthesized in analogy to Example 1 using5-benzo[1,2,5]oxadiazol-5-yl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid(example CH) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine(example AK) as starting materials; MS (ESI) 489.2 (M+H)⁺.

Example 101 Preparation of5-(4-chlorophenyl)-6-cyclobutoxy-N-(pyridin-2-ylmethyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chlorophenyl)-6-cyclobutoxy-nicotinic acid (example CA) and2-pyridinemethanamine (CAN 3731-51-9) as starting materials; LC-MS (UVpeak area/ESI) 99.0%, 394.1 (M+H)⁺.

Example 102 Preparation of5-(4-chlorophenyl)-6-(2-hydroxyethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chlorophenyl)-6-(2-hydroxyethoxy)nicotinic acid (example CI) and3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) asstarting materials; LC-MS (UV peak area/ESI) 100.0%, 443.1 (M+H)⁺.

Example 103 Preparation of(R)-5-(4-chlorophenyl)-6-(tetrahydrofuran-3-yloxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using(R)-5-(4-chlorophenyl)-6-(tetrahydrofuran-3-yloxy)nicotinic acid(example CJ) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine(example AK) as starting materials; LC-MS (UV peak area/ESI) 94.6%,469.1 (M+H)⁺.

Example 104 Preparation of(SR)-5-(4-chlorophenyl)-6-((tetrahydrofuran-3-yl)methoxy)-N-43-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-phenyl)-6-(tetrahydro-furan-3-ylmethoxy)-nicotinic acid(example CK) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine(example AK) as starting materials; enantiomers were separated by chiralHPLC (ChiralPak AD, 30% ethanol/n-heptane (−) enantiomer isolated; LC-MS(UV peak area/ESI) 100%, 483.1038 (M+H)⁺; α_(D) ²⁰(MeOH)=−12.2°

Example 105 Preparation of5-(4-Chloro-phenyl)-6-[(RS)-1-(tetrahydro-furan-3-yl)methoxy]-N-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-nicotinamide

The title compound was synthesized in analogy to Example 1 using5-(4-chloro-phenyl)-6-(tetrahydro-furan-3-ylmethoxy)-nicotinic acid(example CK) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine(example AK) as starting materials; enantiomers were separated by chiralHPLC (ChiralPak AD, 30% ethanol/n-heptane (+) enantiomer isolated; LC-MS(UV peak area/ESI) 100%, 483.1038 (M+H)⁺.

α_(D) ²⁰(MeOH)=+13.2°

The invention claimed is:
 1. A compound of formula I,

wherein: A¹ is N; A² and A³ are CH; R¹ is selected from the groupconsisting of: lower alkyl, cycloalkyl, lower cycloalkylalkyl, lowerhydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lowercarbamoylalkyl, lower alkylcarbonylaminoalkyl, lower phenylalkyl, lowerheterocyclylalkyl wherein the heterocyclyl group is unsubstituted orsubstituted by oxo, lower heteroarylalkyl wherein the heteroaryl groupis unsubstituted or mono- or di-substituted by lower alkyl, and phenylwhich is unsubstituted or mono- or di-substituted by halogen; R² and R⁶independently from each other are hydrogen or halogen; R³ and R⁵independently from each other are selected from the group consisting ofhydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lowerhalogenalkoxy and cyano; R⁴ is selected from the group consisting ofhydrogen, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxyand cyano; or R⁴ and R⁵ together with the C atoms they are attached toform a five- or six-membered carbocycle or a five- or six-memberedheterocycle containing one, two or three heteroatoms selected from thegroup consisting of N, O and S, said carbocycle or heterocycle beingunsubstituted or substituted by one or two substituents independentlyselected from the group consisting of lower alkyl, lower alkoxy,halogen, lower halogenalkyl, lower halogenalkoxy and cyano; R⁷ andR^(7′) independently from each other are hydrogen or lower alkyl; and R⁸is a five- or six-membered heteroaryl group containing one, two or threeheteroatoms selected from the group consisting of N, O and S, saidheteroaryl group being unsubstituted or substituted by one or twosubstituents independently selected from the group consisting of loweralkyl, lower alkoxy, halogen, lower halogenalkyl and cycloalkyl; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, wherein A¹ is N; A² and A³ are CH; R¹ is selected from thegroup consisting of: lower alkyl, cycloalkyl, lower cycloalkylalkyl,lower hydroxyalkyl, lower alkoxyalkyl, lower halogenalkyl, lowercarbamoylalkyl, lower alkylcarbonylaminoalkyl, lower phenylalkyl, lowerheterocyclylalkyl wherein the heterocyclyl group is unsubstituted orsubstituted by oxo, lower heteroarylalkyl wherein the heteroaryl groupis unsubstituted or mono- or di-substituted by lower alkyl, and phenylwhich is unsubstituted or mono- or di-substituted by halogen; R² and R⁶independently from each other are hydrogen or halogen; R³ and R⁵independently from each other are selected from the group consisting ofhydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lowerhalogenalkoxy and cyano; R⁴ is selected from the group consisting ofhydrogen, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxyand cyano; R⁷ and R^(7′) independently from each other are hydrogen orlower alkyl; and R⁸ is a five- or six-membered heteroaryl groupcontaining one, two or three heteroatoms selected from the groupconsisting of N, O and S, said heteroaryl group being unsubstituted orsubstituted by one or two substituents independently selected from thegroup consisting of lower alkyl, lower alkoxy, halogen, lowerhalogenalkyl and cycloalkyl; or a pharmaceutically acceptable saltthereof.
 3. The compound according to claim 1, wherein R¹ is lowercycloalkylalkyl or lower halogenalkyl.
 4. The compound according toclaim 1, wherein R² and R⁶ are hydrogen.
 5. The compound according toclaim 1, wherein R³ and R⁵ are hydrogen.
 6. The compound according toclaim 1, wherein R⁴ is halogen.
 7. The compound according to claim 1,wherein R⁷ and R^(7′) are hydrogen.
 8. The compound according to claim1, wherein R⁸ is a five-membered heteroaryl group containing one, two orthree heteroatoms selected from the group consisting of N, O and S, saidheteroaryl group being unsubstituted or substituted by one or twosubstituents independently selected from the group consisting of loweralkyl, lower alkoxy, halogen, lower halogenalkyl and cycloalkyl.
 9. Thecompound according to claim 1, wherein the five-membered heteroarylgroup is selected from the group consisting of oxazolyl, isoxazolyl,pyrazolyl, thiazolyl and [1,2,4]oxadiazolyl, said heteroaryl group beingunsubstituted or substituted by one or two substituents independentlyselected from the group consisting of lower alkyl, lower alkoxy,halogen, lower halogenalkyl and cycloalkyl.
 10. The compound accordingto claim 1, selected from the group consisting of:6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide,6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (3-cyclopropyl-isoxazol-5-ylmethyl)-amide,6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(2-isopropyl-thiazol-4-ylmethyl)-amide,6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (5-isopropyl-isoxazol-3-ylmethyl)-amide,6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(5-isopropyl-isoxazol-3-ylmethyl)-amide,6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(2-cyclopropyl-oxazol-4-ylmethyl)-amide,6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(2-cyclopropyl-thiazol-4-ylmethyl)-amide,6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(5-trifluoromethyl-isoxazol-3-ylmethyl)-amide,6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid(2-tert-butyl-thiazol-4-ylmethyl)-amide, and6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylicacid (3-isopropyl-isoxazol-5-ylmethyl)-amide, and pharmaceuticallyacceptable salts thereof.
 11. A pharmaceutical composition, comprising acompound according to claim 1 and a pharmaceutically acceptable carrierand/or adjuvant.